Functional Gastric Disorders Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders F. Carbone J. Tack
Key Words Functional dyspepsia · Gastric accommodation · Gastric mechanosensitivity · Gastric emptying · Helicobacter pylori
Abstract Functional dyspepsia (FD), a disorder thought to originate from the gastroduodenum, is one of the most prevalent functional gastrointestinal disorders. In this review, we focused on gastroduodenal mechanisms involved in the pathophysiology of FD. The roles of impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention and to luminal agents, altered mucosal integrity, low-grade inflammation and psychological stress are reviewed. The underlying pathophysiology in FD is probably multifactorial, involving a combination of several of these factors, ultimately leading to symptom pattern and severity. © 2014 S. Karger AG, Basel
Introduction
According to the ROME III diagnostic criteria, functional dyspepsia (FD) is defined as the presence of early satiation, postprandial fullness or epigastric pain or burning, in the absence of organic or metabolic disease that is © 2014 S. Karger AG, Basel 0257–2753/14/0323–0222$39.50/0 E-Mail [email protected] www.karger.com/ddi
likely to explain the symptoms [1]. Even though the majority of dyspeptic patients do not seek medical attention, the prevalence of FD is very high, reaching 15–20% of the adult population, with an incidence of 1% per year [1, 2]. FD has no impact on life expectancy, but is associated with an important impact on quality of life and considerable healthcare expenses [3–5]. The ROME III consensus proposed to subdivide FD into two subgroups: epigastric pain syndrome (EPS) characterized by symptoms of epigastric pain and/or epigastric burning and postprandial distress syndrome (PDS) characterized by postprandial fullness and/or early satiation [1]. The assumption was that these represented two separate entities with specific underlying pathophysiology and with different therapeutic responses. Studies in the general population have shown that EPS and PDS according to the Rome III subdivision are easily identifiable and show good separation [2]. On the other hand, studies in clinical gastroenterological practice and in open-access endoscopy revealed major overlap between EPS and PDS in these populations, thereby limiting the value of these criteria at this level [2]. In addition, there is major overlap of FD with nausea and vomiting disorders and with heartburn, although both are considered separate according to the Rome III consensus [1]. Jan Tack, MD, PhD TARGID, University of Leuven Herestraat 49 BE–3000 Leuven (Belgium) E-Mail jan.tack @ med.kuleuven.ac.be
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
Delayed gastric emptying
Color version available online
Impaired gastric accommodation
Impaired mucosal permeability
Low-grade inflammation
Fig. 1. Schematic representation of patho-
FD symptom perception
Gastric hypersensitivity
Treatment for FD can be initiated when sufficient diagnostic certainty has been reached. According to a consensus algorithm, a thorough clinical evaluation followed by upper gastrointestinal endoscopy is sufficient to make a diagnosis of FD [6]. In addition, it is generally recommended to evaluate the presence of Helicobacter pylori infection, but other tests such as laboratory studies and upper abdominal ultrasound are only needed in selected cases [6]. In terms of treatment, it has often been proposed that treatment of the underlying pathophysiological disorder should generate the highest therapeutic response in FD [7]. However, the pathophysiology is complex, multifactorial and far from completely elucidated. Gastric motor and sensory dysfunction as well as impaired mucosal integrity, low-grade immune activation and dysregulation of the gut-brain axis have all been implicated [8, 9]. In this review, we summarize the different mechanism underlying FD.
During a meal, the proximal stomach relaxes to serve as a food reservoir, thereby allowing an increase in the gastric volume without a rise of the intragastric pressure. This phenomenon, referred to as gastric accommodation (GA), is controlled by a vago-vagal reflex triggered by meal ingestion [10–12]. GA is mediated by the activation of nonadrenergic noncholinergic nerves in the gastric wall that lead to the production and diffusion of nitric oxide (NO) to the gastric smooth muscle where it has an inhibitory effect through a cGMP-dependent pathway
[10–12]. In addition, inhibition of cholinergic pathways may also contribute to the magnitude of meal-induced fundic relaxation. The arrival and accumulation of food in the proximal stomach is sensed by visceral mechanoreceptors in the gastric wall. Observations in humans support the concept that these mechanoreceptors are sensitive to changes in wall tension, which increases during food arrival in the stomach, but which is reduced by relaxation of the smooth muscle [13]. The same type of mechanoreceptors have also been implicated in gastric visceral sensitivity, as progressive balloon distention of the proximal stomach leads to the activation of the visceral pain neuromatrix which is associated with pain and discomfort generation [11]. At a more physiological level, activation of these pathways is thought to contribute to the sensation of satiation that eventually leads to the termination of the meal [11, 14]. In FD, impaired GA to a meal is considered a major pathophysiological mechanism (fig. 1). It has been observed in up to 40% of the patients [12]. Studies in patient cohorts have implicated impairment of GA in the generation of symptoms such as early satiety, nausea, bloating and weight loss [15]. In support of its symptomatic relevance, inhibition of NO-synthase by administration of L-NMMA to healthy volunteers inhibits GA and induces early satiation [16]. However, the GA reflex was not fully abolished by L-NMMA, suggesting that other neurotransmitters than NO are probably also involved [16]. One important candidate is vasoactive intestinal polypeptide, which also acts as an inhibitory neurotransmitter
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
Impaired Gastric Accommodation
223
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
physiological mechanisms implicated in the genesis of FD symptoms.
Gastric Emptying
After the meal, tonic contractions of the proximal stomach cause the redistribution of the gastric content to the distal stomach [11]. In the antrum, the meal is reduced into small particles that are able to pass through the pylorus into the duodenum [33, 34]. The emptying process of a solid meal can be divided into two phases. During the lag phase, peristaltic waves originated from the stomach corpus to the antrum, mix and force the antral 224
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
meal contents towards the pylorus. This phase is followed by a constant emptying time of the nutrients into the duodenum [33, 34]. During gastric emptying, nutrient and caloric sensing in the small intestine occurs and releases signaling hormones and molecules into the circulation such as cholecystokinin, glucagon-like peptide and peptide YY, which enhance the satiation and reward effect after the meal [11, 15, 33]. Gastroparesis is defined as the presence of delayed gastric emptying in the absence of a mechanical obstruction, and has been associated with symptoms of nausea and vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain [34–36]. A diagnosis of gastroparesis is made when organic obstruction has been excluded by endoscopy or radiography, and when delayed emptying is evident from a gastric emptying test using scintigraphy or breath test [33, 37]. The origin of gastroparesis may vary, but there are three principal causes that stand out. Longstanding diabetes mellitus may affect the function of every organ of the body, and gastrointestinal complications are very common in this group of patients [38]. The 10-year incidence estimate of diabetic gastroparesis is 5.2% in type 1 diabetes and 1% in type 2 diabetes [36, 39]. Gastroparesis is also common after a surgery or trauma that may damage the vagal nerves controlling fundic relaxations and antral contractions [33, 36, 40]. The largest group are those patients with idiopathic gastroparesis, and this group overlaps with FD in terms of symptoms and findings [41, 42]. The cause and mechanisms in idiopathic gastroparesis are unknown, but damage to nerves and interstitial cells of Cajal, possibly as a consequence of prior viral or bacterial infection has been proposed as a leading hypothesis [35, 36]. In large patient series, the prevalence of delayed emptying in FD ranges between 20 and 35% (fig. 1) [37, 41, 42]. Both FD and idiopathic gastroparesis are upper gut functional disorders with very similar symptom classification and treatment management, which is a matter of confusion and controversy to patients, physicians and researchers. The Rome III consensus attempted to separate FD from (idiopathic) gastroparesis by allocating a separate diagnostic category to disorders of nausea and vomiting [1, 35, 41, 42]. Cohort studies have indeed shown an association of delayed emptying with symptoms of nausea and vomiting, but also with postprandial fullness and female gender [43–45]. Based on this overlap, it is clear that the symptom pattern is a poor predictor of the presence of delayed gastric emptying [43–46]. Moreover, the severity of delayed emptying is a poor predictor of symptom severity in FD with delayed gastric Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
in the proximal stomach [17, 18], relaxing smooth muscle through the cAMP pathway. Serotonin (5-HT) is another candidate mediator [19, 20]. Indeed, inhibition of 5-HT synthesis through tryptophan depletion enhances GA without altering gastric sensitivity [21]. Paroxetine, a selective serotonin reuptake inhibitor, was shown to enhance GA [22]. Cisapride, a 5-HT4 agonist and 5-HT3 antagonist, and tegaserod, a partial 5-TH4 agonist, are all able to enhance GA [23–25]. Finally, buspirone, a 5-HT1A agonist, significantly enhances GA and improves FD symptoms [26, 27]. The endocannabinoid system and endogenous opioids also seem to be involved: rimonabant, an endocannabinoid antagonist used in the treatment of obesity, inhibits GA [28], and the same was shown for the peripherally acting mu opioid antagonist methylnaltrexone [29]. Duodenogastric feedback may also contribute to controlling GA, as nutrient infusion in the small intestine could also induce relaxation of the proximal stomach [30]. The site of symptom generation in FD with impaired GA has not been determined with certainty. As outlined above, tension-sensitive mechanoreceptors in the proximal stomach may signal discomfort and pain in case of impaired GA [13]. In addition, redistribution of the meal to the antrum may also contribute to symptom generation. Salet et al. [15] compared the gastric distribution of food in healthy volunteers and FD patients. During these experiments, decreased GA in FD patients was associated with a rapid redistribution of the ingested content to the distal stomach. Similar results were obtained earlier by Troncon et al. [31] using scintigraphy, which also showed redistribution of food to the antrum in FD. In line with these studies, Caldarella et al. [32] showed that both the proximal stomach and the antrum are hypersensitive to distention in FD patients compared to healthy subjects. Hence, when impaired GA leads to antral volume overload, this is highly likely to provoke symptoms in FD patients.
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
Visceral Hypersensitivity
225
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
Visceral sensation can be determined by means of transmission of chemical and mechanical sensing. Conceptually, the gastric wall contains two types of mechanoreceptors: mechanoreceptors arranged in parallel to the smooth muscle that respond to elongation, and mechanoreceptors arranged in series to the smooth muscle that respond to wall tension [13, 48]. Chemosensitive modalities are multiple and varied, including nutrient sensing, acid sensitivity, taste sensing, etc. [33]. Signals from the mechano- and chemoreceptors travel from the gut in a 3-neuron-chain to the central nervous system [48]. The first-order neuron, with cell body in the dorsal root ganglia, travels via an afferent pathway from the gut to the spinal cord. Here, signals ascend via the secondorder neuron to the thalamus and brain through the spinothalamic and spinoreticular tracts and synapse with the autonomic and satiety centers. Finally, the limbic system (emotional responses) and the sensory cortex (conscious perception) are reached by the third-order neuron [48]. Gastric mechanosensitivity is studied by balloon distention using the gastric barostat, which allows delivering stepwise isobaric or isovolumetric increments of the gastric balloon in the stomach in the fasted state. Both pressure and volume of the balloon influence sensitivity to gastric distention [49]. Hence, it has been suggested that gastric wall tension during the gastric distention is the sensory modality leading to perception [48–50]. Gastric
wall tension during balloon distention can be estimated by using the law of Laplace, and application of this formula supports the hypothesis that insufficient GA to a meal increases intragastric wall tension [48–50]. However, applying this formula requires a number of assumptions that are not necessarily fulfilled: the stomach has a perfect spherical shape, the gastric wall is infinitely thin, and no active contractile activity occurs [48]. By means of the gastric barostat, the gastric compliance can also be studied. The gastric compliance is defined as the relation between stepwise isobaric pressures and the corresponding intraballoon volume [48]. It has been shown in a number of studies that a subgroup of FD patients are hypersensitive to balloon distention, in spite of normal compliance (fig. 1) [49–52]. Hypersensitivity to gastric distention is defined as a decrease in the first perception threshold and the discomfort threshold below the normal range in healthy volunteers [51]. In the largest cohort study to date, hypersensitivity to distention in FD was associated with symptoms of postprandial pain, excessive belching and unexplained weight loss [51]. In keeping with a role for tension receptors, drugs that decrease gastric wall tension, such as sumatriptan and clonidine, decrease sensitivity to gastric distention and decrease the severity of meal-induced dyspeptic symptoms [50]. The majority of FD patients reported that symptoms were triggered or aggravated after the meal [53]. Therefore, it has been suggested that postprandial hypersensitivity might be most relevant to the generation of FD symptoms. However, there is a large number of variables that may affect gastric sensitivity after a meal, such as GA, gastric acid secretion, duodenal acid exposure, altered gastroduodenal hormone secretion, and the nutrient composition of the meal [11, 33, 52–56]. In a recent study, Farré et al. [56] studied the sensitivity to distention after a meal in FD patients and compared it to healthy volunteers. The study showed that in FD after a meal the gastric sensitivity to distention is enhanced and is significantly correlated to the cumulative meal-related dyspeptic symptom score. This implies that postprandial sensitivity to gastric distention, which depended on both hypersensitivity in the fasting state and GA, is an important contributor to symptom generation in FD. The other modality that has been extensively studied in FD is visceral chemosensitivity. Capsaicin, the natural compound of chili pepper, is an agonist at the transient receptor potential type 1 (TRP1) channel which converts thermal and chemical stimuli into painful sensations or discomfort [57–59]. Moreover, it has been previously ob-
emptying or idiopathic gastroparesis, and other mechanisms such as impaired accommodation and visceral hypersensitivity are important factors driving symptom pattern and severity [46]. Idiopathic gastroparesis and diabetic gastroparesis are usually managed by prokinetic drugs, assuming that acceleration of the gastric emptying will ameliorate the symptoms. Data from a recent systematic analysis show that the use of prokinetic drugs such as metoclopramide, domperidone, cisapride, erythromycin, and levosulpiride indeed improves symptoms and gastric emptying in gastroparesis patients, but none of these drugs showed a significant correlation between symptom improvement and the effect on gastric emptying [47]. This implies that improvement of the symptoms is not necessarily due to their effect on gastric emptying but also on other different factors such as an effect on GA or on gastric sensitivity, or central effects.
Low-Grade Inflammation and Mucosal Permeability
The mucosal barrier serves as the first line of defense against pathogens. The gastroduodenal mucosal barrier results from a complex interplay between extracellular and cellular components [66]. Between the cells, a combination of tight and adherens junction regulates and seals the paracellular space. These junctions are therefore the rate-limiting step in transepithelial transport and the principal determinant of mucosal permeability [67]. In IBS and IBD studies, it has been hypothesized that mucosal barrier dysfunction could facilitate the passage of luminal antigens and elicit an immune response. This response could cause a low-grade inflammation that generates IBS symptoms [6, 68]. This hypothesis has also been 226
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
taken into account for the study of underlying mechanisms in FD [8]. H. pylori has long been suggested to be one of the pathogenetic factors in FD [69–72]. At present, studies have shown that H. pylori plays an important role in damaging the integrity of the gastric epithelial barrier [73, 74]. However, the role of H. pylori in FD remains unestablished, based on the lack of association of H. pylori presence with symptom pattern and gastric sensorimotor function, and the limited and late-onset response to eradication therapy [6, 69, 72]. Other pathogenic organisms may also be relevant to FD pathogenesis: it has been previously observed that gastric infections other than H. pylori increase the prevalence of FD [75–77]. A study from Leuven showed that FD patients that had a history suggestive of postinfectious dyspepsia showed prevalent symptoms of early satiety, weight loss, nausea and vomiting compared to unspecified-onset FD [77]. Moreover, impaired GA was also more prevalent in this group, and this was attributable to a defect at the level of gastric intrinsic nitrergic neurons [77]. Kindt et al. [78] found that this group of patients with postinfectious FD showed signs of activation of duodenal immune cells. The results of duodenal biopsies of postinfectious FD patients showed focal aggregates of CD8+ T cells, a decrease in CD4+ and an increase in macrophages surrounding the crypts. Moreover, postinfectious FD patients showed delayed gastric emptying compared to unspecified-onset FD [78]. Other studies have also shown an increase in macrophages and eosinophils in the duodenal mucosa in FD, suggesting the presence of low-grade inflammation (fig. 1) [79–81]. Li et al. [81] reported low-grade inflammation in patients with postinfectious and unspecifiedonset FD. In gastric mucosal biopsy samples, the authors found increased numbers of mast cells in close proximity to nerves, and augmented expression of histamine, serotonin and tryptase compared with healthy controls. In postinfectious FD biopsies, the release of histamine and serotonin was higher, and the distance of mast cells to nerves was shorter than in unspecified FD [81]. Recent studies have addressed duodenal mucosal integrity in FD. Vanheel et al. [82] reported impaired mucosal barrier function and low-grade inflammation in the duodenum in FD patients (fig. 1). FD patients are characterized by the increased infiltration of mucosal mast cells and eosinophils in the mucosa, and this is correlated with altered expression of certain cell-to-cell adhesion proteins such as occludin and zonulin-1, β-catenin, Ecadherin and desmoglein-2. Although these data show a Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
served that the TRP1 channel could also be involved in gastric motility regulation. Studies with capsaicin in FD patients showed an increase in hypersensitivity and dyspeptic upper gut symptoms [57–61]. However, the known hypersensitivity in the subjects was not a predictor for the symptoms and their intensity [57]. Acid-suppressive therapy is a frequently used treatment modality in FD patients. Acid sensitivity in the stomach and duodenum has also been implicated in FD symptom generation. Oshima et al. [62] studied the effect of acid and water infusion in the stomach of FD patients and healthy subjects. The results showed that FD patients were more sensitive to the acid infusion compared to healthy volunteers, and they reported an increase in the quantity and severity of dyspeptic symptoms compared to water infusion. Studies using duodenal acid infusion in FD reported a reduced duodenal acid clearance and hypersensitivity to duodenal acid in patients, the most prominently induced dyspeptic symptom being nausea [55, 63, 64]. A study in FD patients with prominent nausea showed that patients had an increased endogenous acid exposure during daytime with reduced duodenal clearance [55]. It was also observed that the severity of the symptoms was related to the increased endogenous acid exposure. However, infusion of exogenous acid in the duodenum did not aggravate the symptoms. Prolonged duodenal acid infusion in healthy subjects induces dyspeptic symptoms such discomfort, bloating, nausea and epigastric burning [65]. Finally, it has also been shown that after infusion of exogenous acid in the duodenum the threshold for discomfort to gastric balloon distention decreased [54]. Moreover, the GA to a meal decreased after acid exposure compared to saline.
clear relation between mucosal permeability and lowgrade inflammation, a causal relationship in either direction remains to be established [82]. Most recently, Vanuytsel et al. [83] studied the impact of acute psychological stress on duodenal mucosal integrity in a group of healthy volunteers. The authors showed that stress-induced activation of the hypothalamo-pituitary-adrenal axis increased duodenal mucosal permeability and that this effect was dependent on mast cell activation. The effect of stress-induced hyperpermeability could be mimicked by exogenous administration of corticotropin-releasing hormone (CRH), and both stress-induced and CRH-induced hyperpermeability could be suppressed by previous mast cell stabilization [83]. The role of stress and mast cells in FD patients with increased duodenal permeability remains to be studied.
Conclusion
FD is one of the most common gastrointestinal disorders encountered in clinical practice. From a pathophysiological viewpoint, FD is a heterogeneous disorder in which different mechanisms are associated with different symptom profiles (fig. 1). Over the last years, the amount of knowledge regarding the pathophysiology of FD has increased tremendously. However, at the same time, a number of new hypotheses and questions were raised by this research. It is conceivable that a better understanding of the underlying pathogenesis and symptom generation in FD may lead to the development of improved treatment options and better symptom control.
Disclosure Statement None.
References
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
10 Kindt S, Tack J: Impaired gastric accommodation and its role in dyspepsia. Gut 2006;55: 1685–1691. 11 Janssen P, Vanden Berghe P, Verschueren S, Lehmann A, Depoortere I, Tack J: Review article: the role of gastric motility in the control of food intake. Aliment Pharmacol Ther 2011; 33:880–894. 12 Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J: Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115:1346–1352. 13 Piessevaux H, Tack J, Wilmer A, Coulie B, Geubel A, Janssens J: Perception of changes in wall tension of the proximal stomach in humans. Gut 2001;49:203–208. 14 Paintal AS: A study of gastric stretch receptors; their role in the peripheral mechanism of satiation of hunger and thirst. J Physiol 1954; 126:255–270. 15 Salet GA, Samsom M, Roelofs JM, van Berge Henegouwen GP, Smout AJ, Akkermans LM: Responses to gastric distension in functional dyspepsia. Gut 1998;42:823–829. 16 Tack J, Demedts I, Meulemans A, Schuurkes J, Janssens J: Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans. Gut 2002;51:219–224. 17 Tonini M, De Giorgio R, De Ponti F, Sternini C, Spelta V, Dionigi P, et al: Role of nitric oxide- and vasoactive intestinal polypeptidecontaining neurones in human gastric fundus strip relaxations. Br J Pharmacol 2000; 129: 12–20.
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
18 Takahashi T, Owyang C: Vagal control of nitric oxide and vasoactive intestinal polypeptide release in the regulation of gastric relaxation in rat. J Physiol 1995;484:481–492. 19 Grover M, Camilleri M: Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases. J Gastroenterol 2013;48:177–181. 20 Gershon MD, Tack J: The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397–414. 21 Geeraerts B, Van Oudenhove L, Boesmans W, Vos R, Vanden Berghe P, Tack J: Influence of acute tryptophan depletion on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2011; 300:G228– G235. 22 Tack J, Broekaert D, Coulie B, Fischler B, Janssens J: Influence of the selective serotonin re-uptake inhibitor, paroxetine, on gastric sensorimotor function in humans. Aliment Pharmacol Ther 2003;17:603–608. 23 Tack J, Broeckaert D, Coulie B, Janssens J: The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther 1998;12:761–766. 24 Tack J, Janssen P, Bisschops R, Vos R, Phillips T, Tougas G: Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia. Neurogastroenterol Motil 2011;23:e32–e39.
227
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
1 Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al: Functional gastroduodenal disorders. Gastroenterology 2006; 130:1466–1479. 2 Tack J, Talley NJ: Functional dyspepsia – symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013;10:134–141. 3 Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P: Effect of dyspepsia on survival: a longitudinal 10-year follow-up study. Am J Gastroenterol 2012;107:912–921. 4 El-Serag HB, Talley NJ: Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther 2003;18:387–393. 5 Moayyedi P, Mason J: Clinical and economic consequences of dyspepsia in the community. Gut 2002;50(suppl 4):iv10–iv12. 6 Tack J, Talley NJ: Functional dyspepsia – symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013;10:134–141. 7 Talley NJ: Review article: functional dyspepsia – should treatment be targeted on disturbed physiology? Aliment Pharmacol Ther 1995;9:107–115. 8 Vanheel H, Farré R: Changes in gastrointestinal tract function and structure in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:142–149. 9 Van Oudenhove L, Aziz Q: The role of psychosocial factors and psychiatric disorders in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:158–167.
228
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
41 Lacy BE: Functional dyspepsia and gastroparesis: one disease or two? Am J Gastroenterol 2012;107:1615–1620. 42 Janssen P, van Oudenhove L, Bisschops R, Tack J: Idiopathic gastroparesis or functional dyspepsia with delayed gastric emptying: where is the difference? Gastroenterology 2011; 140: 2145–2146; author reply 2146– 2148. 43 Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J: Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003;98: 783–788. 44 Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, Marengo M, Corinaldesi R: Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996;110:1036–1042. 45 Talley NJ, Locke GR 3rd, Lahr BD, Zinsmeister AR, Tougas G, Ligozio G, Rojavin MA, Tack J: Functional dyspepsia, delayed gastric emptying, and impaired quality of life. Gut 2006;55:933–939. 46 Karamanolis G, Caenepeel P, Arts J, Tack J: Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction? Gut 2007;56:29–36. 47 Janssen P, Harris MS, Jones M, Masaoka T, Farre R, Tornblom H, et al: The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–1391. 48 Camilleri M, Coulie B, Tack JF: Visceral hypersensitivity: facts, speculations, and challenges. Gut 2001;48:125–131. 49 Notivol R, Coffin B, Azpiroz F, Mearin F, Serra J, Malagelada JR: Gastric tone determines the sensitivity of the stomach to distention. Gastroenterology 1995;108:330–336. 50 Tack J, Caenepeel P, Corsetti M, Janssens J: Role of tension receptors in dyspeptic patients with hypersensitivity to gastric distention. Gastroenterology 2004;127:1058–1066. 51 Mertz H, Fullerton S, Naliboff B, Mayer EA: Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 1998; 42:814–822. 52 Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J: Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121: 526– 535. 53 Bisschops R, Karamanolis G, Arts J, Caenepeel P, Verbeke K, Janssens J, Tack J: Relationship between symptoms and ingestion of a meal in functional dyspepsia. Gut 2008; 57: 1495–1503. 54 Lee KJ, Vos R, Janssens J, Tack J: Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol 2004; 286:G278–G284.
55 Lee KJ, Demarchi B, Demedts I, Sifrim D, Raeymaekers P, Tack J: A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am J Gastroenterol 2004; 99:1765–1773. 56 Farré R, Vanheel H, Vanuytsel T, Masaoka T, Tornblom H, Simren M, et al: In functional dyspepsia, hypersensitivity to postprandial distention correlates with meal-related symptom severity. Gastroenterology 2013; 145: 566–573. 57 Hammer J, Fuhrer M, Pipal L, Matiasek J: Hypersensitivity for capsaicin in patients with functional dyspepsia. Neurogastroenterol Motil 2008;20:125–133. 58 Holzer P: Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991; 43: 143– 201. 59 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–824. 60 Anand P, Aziz Q, Willert R, van Oudenhove L: Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil 2007;19(suppl 1):29–46. 61 Fuhrer M, Vogelsang H, Hammer J: A placebo-controlled trial of an oral capsaicin load in patients with functional dyspepsia. Neurogastroenterol Motil 2011;23:918-e397. 62 Oshima T, Okugawa T, Tomita T, Sakurai J, Toyoshima F, Watari J, et al: Generation of dyspeptic symptoms by direct acid and water infusion into the stomachs of functional dyspepsia patients and healthy subjects. Aliment Pharmacol Ther 2012;35:175–182. 63 Schwartz MP, Samsom M, Smout AJ: Chemospecific alterations in duodenal perception and motor response in functional dyspepsia. Am J Gastroenterol 2001;96:2596–2602. 64 Samsom M, Verhagen MA, vanBerge Henegouwen GP, Smout AJ: Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 1999; 116: 515– 520. 65 di Stefano M, Vos R, Vanuytsel T, Janssens J, Tack J: Prolonged duodenal acid perfusion and dyspeptic symptom occurrence in healthy volunteers. Neurogastroenterol Motil 2009; 21:712-e40. 66 Turner JR: Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799–809. 67 Ohman L, Simren M: Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010;7:163–173. 68 Salim SY, Soderholm JD: Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17: 362–381. 69 Suzuki H, Moayyedi P: Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:168–174.
Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
25 Tack J, Vos R, Janssens J, Salter J, Jauffret S, Vandeplassche G: Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment Pharmacol Ther 2003;18:1031–1037. 26 Van Oudenhove L, Kindt S, Vos R, Coulie B, Tack J: Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther 2008;28:1326–1333. 27 Tack J, Janssen P, Masaoka T, Farre R, Van Oudenhove L: Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012; 10:1239–1245. 28 Ameloot K, Janssen P, Scarpellini E, Vos R, Boesmans W, Depoortere I, et al: Endocannabinoid control of gastric sensorimotor function in man. Aliment Pharmacol Ther 2010;31:1123–1131. 29 Janssen P, Pottel H, Vos R, Tack J: Endogenously released opioids mediate meal-induced gastric relaxation via peripheral muopioid receptors. Aliment Pharmacol Ther 2011;33:607–614. 30 Carrasco M, Azpiroz F, Malagelada JR: Modulation of gastric accommodation by duodenal nutrients. World J Gastroenterol 2005;11: 4848–4851. 31 Troncon LE, Bennett RJ, Ahluwalia NK, Thompson DG: Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994; 35: 327–332. 32 Caldarella MP, Azpiroz F, Malagelada JR: Antro-fundic dysfunctions in functional dyspepsia. Gastroenterology 2003;124:1220–1229. 33 Farré R, Tack J: Food and symptom generation in functional gastrointestinal disorders: physiological aspects. Am J Gastroenterol 2013;108:698–706. 34 Bouras EP, Vazquez Roque MI, Aranda-Michel J: Gastroparesis: from concepts to management. Nutr Clin Pract 2013;28:437–447. 35 Parkman HP, Camilleri M, Farrugia G, McCallum RW, Bharucha AE, Mayer EA, et al: Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–133. 36 Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L: Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18–37; quiz 38. 37 Masaoka T, Tack J: Gastroparesis: current concepts and management. Gut Liver 2009;3: 166–173. 38 Krishnan B, Babu S, Walker J, Walker AB, Pappachan JM: Gastrointestinal complications of diabetes mellitus. World J Diabetes 2013;4:51–63. 39 Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, Melton LJ 3rd, Talley NJ: Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. Am J Gastroenterol 2012;107:82–88. 40 Hasler WL: Gastroparesis: pathogenesis, diagnosis and management. Nat Rev Gastroenterol Hepatol 2011;8:438–453.
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
75 Dizdar V, Gilja OH, Hausken T: Increased visceral sensitivity in Giardia-induced postinfectious irritable bowel syndrome and functional dyspepsia. Effect of the 5HT3-antagonist ondansetron. Neurogastroenterol Motil 2007;19:977–982. 76 Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, et al: Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005;129:98– 104. 77 Tack J, Demedts I, Dehondt G, Caenepeel P, Fischler B, Zandecki M, et al: Clinical and pathophysiological characteristics of acuteonset functional dyspepsia. Gastroenterology 2002;122:1738–1747. 78 Kindt S, Tertychnyy A, de Hertogh G, Geboes K, Tack J: Intestinal immune activation in presumed post-infectious functional dyspepsia. Neurogastroenterol Motil 2009; 21: 832e56. 79 Talley NJ, Walker MM, Aro P, Ronkainen J, Storskrubb T, Hindley LA, et al: Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 2007;5: 1175–1183.
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
80 Walker MM, Talley NJ, Prabhakar M, Pennaneac’h CJ, Aro P, Ronkainen J, et al: Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009;29:765–773. 81 Li X, Chen H, Lu H, Li W, Chen X, Peng Y, et al: The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand J Gastroenterol 2010; 45: 573–581. 82 Vanheel H, Vicario M, Vanuytsel T, Van Oudenhove L, Martinez C, Keita AV, et al: Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut 2013, Epub ahead of print. 83 Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al: Psychological stress and corticotropinreleasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 2013, Epub ahead of print.
229
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
70 Tucci A, Corinaldesi R, Stanghellini V, Tosetti C, Di Febo G, Paparo GF, et al: Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992;103:768–774. 71 Mearin F, de Ribot X, Balboa A, Salas A, Varas MJ, Cucala M, et al: Does Helicobacter pylori infection increase gastric sensitivity in functional dyspepsia? Gut 1995;37:47–51. 72 Sarnelli G, Cuomo R, Janssens J, Tack J: Symptom patterns and pathophysiological mechanisms in dyspeptic patients with and without Helicobacter pylori. Dig Dis Sci 2003; 48:2229–2236. 73 Wu J, Xu S, Zhu Y: Helicobacter pylori CagA: a critical destroyer of the gastric epithelial barrier. Dig Dis Sci 2013;58:1830–1837. 74 Fiorentino M, Ding H, Blanchard TG, Czinn SJ, Sztein MB, Fasano A: Helicobacter pyloriinduced disruption of monolayer permeability and proinflammatory cytokine secretion in polarized human gastric epithelial cells. Infect Immun 2013;81:876–883.
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders F. Carbone J. Tack
Key Words Functional dyspepsia · Gastric accommodation · Gastric mechanosensitivity · Gastric emptying · Helicobacter pylori
Abstract Functional dyspepsia (FD), a disorder thought to originate from the gastroduodenum, is one of the most prevalent functional gastrointestinal disorders. In this review, we focused on gastroduodenal mechanisms involved in the pathophysiology of FD. The roles of impaired gastric accommodation, delayed gastric emptying, hypersensitivity to gastric distention and to luminal agents, altered mucosal integrity, low-grade inflammation and psychological stress are reviewed. The underlying pathophysiology in FD is probably multifactorial, involving a combination of several of these factors, ultimately leading to symptom pattern and severity. © 2014 S. Karger AG, Basel
Introduction
According to the ROME III diagnostic criteria, functional dyspepsia (FD) is defined as the presence of early satiation, postprandial fullness or epigastric pain or burning, in the absence of organic or metabolic disease that is © 2014 S. Karger AG, Basel 0257–2753/14/0323–0222$39.50/0 E-Mail [email protected] www.karger.com/ddi
likely to explain the symptoms [1]. Even though the majority of dyspeptic patients do not seek medical attention, the prevalence of FD is very high, reaching 15–20% of the adult population, with an incidence of 1% per year [1, 2]. FD has no impact on life expectancy, but is associated with an important impact on quality of life and considerable healthcare expenses [3–5]. The ROME III consensus proposed to subdivide FD into two subgroups: epigastric pain syndrome (EPS) characterized by symptoms of epigastric pain and/or epigastric burning and postprandial distress syndrome (PDS) characterized by postprandial fullness and/or early satiation [1]. The assumption was that these represented two separate entities with specific underlying pathophysiology and with different therapeutic responses. Studies in the general population have shown that EPS and PDS according to the Rome III subdivision are easily identifiable and show good separation [2]. On the other hand, studies in clinical gastroenterological practice and in open-access endoscopy revealed major overlap between EPS and PDS in these populations, thereby limiting the value of these criteria at this level [2]. In addition, there is major overlap of FD with nausea and vomiting disorders and with heartburn, although both are considered separate according to the Rome III consensus [1]. Jan Tack, MD, PhD TARGID, University of Leuven Herestraat 49 BE–3000 Leuven (Belgium) E-Mail jan.tack @ med.kuleuven.ac.be
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
Delayed gastric emptying
Color version available online
Impaired gastric accommodation
Impaired mucosal permeability
Low-grade inflammation
Fig. 1. Schematic representation of patho-
FD symptom perception
Gastric hypersensitivity
Treatment for FD can be initiated when sufficient diagnostic certainty has been reached. According to a consensus algorithm, a thorough clinical evaluation followed by upper gastrointestinal endoscopy is sufficient to make a diagnosis of FD [6]. In addition, it is generally recommended to evaluate the presence of Helicobacter pylori infection, but other tests such as laboratory studies and upper abdominal ultrasound are only needed in selected cases [6]. In terms of treatment, it has often been proposed that treatment of the underlying pathophysiological disorder should generate the highest therapeutic response in FD [7]. However, the pathophysiology is complex, multifactorial and far from completely elucidated. Gastric motor and sensory dysfunction as well as impaired mucosal integrity, low-grade immune activation and dysregulation of the gut-brain axis have all been implicated [8, 9]. In this review, we summarize the different mechanism underlying FD.
During a meal, the proximal stomach relaxes to serve as a food reservoir, thereby allowing an increase in the gastric volume without a rise of the intragastric pressure. This phenomenon, referred to as gastric accommodation (GA), is controlled by a vago-vagal reflex triggered by meal ingestion [10–12]. GA is mediated by the activation of nonadrenergic noncholinergic nerves in the gastric wall that lead to the production and diffusion of nitric oxide (NO) to the gastric smooth muscle where it has an inhibitory effect through a cGMP-dependent pathway
[10–12]. In addition, inhibition of cholinergic pathways may also contribute to the magnitude of meal-induced fundic relaxation. The arrival and accumulation of food in the proximal stomach is sensed by visceral mechanoreceptors in the gastric wall. Observations in humans support the concept that these mechanoreceptors are sensitive to changes in wall tension, which increases during food arrival in the stomach, but which is reduced by relaxation of the smooth muscle [13]. The same type of mechanoreceptors have also been implicated in gastric visceral sensitivity, as progressive balloon distention of the proximal stomach leads to the activation of the visceral pain neuromatrix which is associated with pain and discomfort generation [11]. At a more physiological level, activation of these pathways is thought to contribute to the sensation of satiation that eventually leads to the termination of the meal [11, 14]. In FD, impaired GA to a meal is considered a major pathophysiological mechanism (fig. 1). It has been observed in up to 40% of the patients [12]. Studies in patient cohorts have implicated impairment of GA in the generation of symptoms such as early satiety, nausea, bloating and weight loss [15]. In support of its symptomatic relevance, inhibition of NO-synthase by administration of L-NMMA to healthy volunteers inhibits GA and induces early satiation [16]. However, the GA reflex was not fully abolished by L-NMMA, suggesting that other neurotransmitters than NO are probably also involved [16]. One important candidate is vasoactive intestinal polypeptide, which also acts as an inhibitory neurotransmitter
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
Impaired Gastric Accommodation
223
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
physiological mechanisms implicated in the genesis of FD symptoms.
Gastric Emptying
After the meal, tonic contractions of the proximal stomach cause the redistribution of the gastric content to the distal stomach [11]. In the antrum, the meal is reduced into small particles that are able to pass through the pylorus into the duodenum [33, 34]. The emptying process of a solid meal can be divided into two phases. During the lag phase, peristaltic waves originated from the stomach corpus to the antrum, mix and force the antral 224
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
meal contents towards the pylorus. This phase is followed by a constant emptying time of the nutrients into the duodenum [33, 34]. During gastric emptying, nutrient and caloric sensing in the small intestine occurs and releases signaling hormones and molecules into the circulation such as cholecystokinin, glucagon-like peptide and peptide YY, which enhance the satiation and reward effect after the meal [11, 15, 33]. Gastroparesis is defined as the presence of delayed gastric emptying in the absence of a mechanical obstruction, and has been associated with symptoms of nausea and vomiting, early satiety, postprandial fullness, bloating, and upper abdominal pain [34–36]. A diagnosis of gastroparesis is made when organic obstruction has been excluded by endoscopy or radiography, and when delayed emptying is evident from a gastric emptying test using scintigraphy or breath test [33, 37]. The origin of gastroparesis may vary, but there are three principal causes that stand out. Longstanding diabetes mellitus may affect the function of every organ of the body, and gastrointestinal complications are very common in this group of patients [38]. The 10-year incidence estimate of diabetic gastroparesis is 5.2% in type 1 diabetes and 1% in type 2 diabetes [36, 39]. Gastroparesis is also common after a surgery or trauma that may damage the vagal nerves controlling fundic relaxations and antral contractions [33, 36, 40]. The largest group are those patients with idiopathic gastroparesis, and this group overlaps with FD in terms of symptoms and findings [41, 42]. The cause and mechanisms in idiopathic gastroparesis are unknown, but damage to nerves and interstitial cells of Cajal, possibly as a consequence of prior viral or bacterial infection has been proposed as a leading hypothesis [35, 36]. In large patient series, the prevalence of delayed emptying in FD ranges between 20 and 35% (fig. 1) [37, 41, 42]. Both FD and idiopathic gastroparesis are upper gut functional disorders with very similar symptom classification and treatment management, which is a matter of confusion and controversy to patients, physicians and researchers. The Rome III consensus attempted to separate FD from (idiopathic) gastroparesis by allocating a separate diagnostic category to disorders of nausea and vomiting [1, 35, 41, 42]. Cohort studies have indeed shown an association of delayed emptying with symptoms of nausea and vomiting, but also with postprandial fullness and female gender [43–45]. Based on this overlap, it is clear that the symptom pattern is a poor predictor of the presence of delayed gastric emptying [43–46]. Moreover, the severity of delayed emptying is a poor predictor of symptom severity in FD with delayed gastric Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
in the proximal stomach [17, 18], relaxing smooth muscle through the cAMP pathway. Serotonin (5-HT) is another candidate mediator [19, 20]. Indeed, inhibition of 5-HT synthesis through tryptophan depletion enhances GA without altering gastric sensitivity [21]. Paroxetine, a selective serotonin reuptake inhibitor, was shown to enhance GA [22]. Cisapride, a 5-HT4 agonist and 5-HT3 antagonist, and tegaserod, a partial 5-TH4 agonist, are all able to enhance GA [23–25]. Finally, buspirone, a 5-HT1A agonist, significantly enhances GA and improves FD symptoms [26, 27]. The endocannabinoid system and endogenous opioids also seem to be involved: rimonabant, an endocannabinoid antagonist used in the treatment of obesity, inhibits GA [28], and the same was shown for the peripherally acting mu opioid antagonist methylnaltrexone [29]. Duodenogastric feedback may also contribute to controlling GA, as nutrient infusion in the small intestine could also induce relaxation of the proximal stomach [30]. The site of symptom generation in FD with impaired GA has not been determined with certainty. As outlined above, tension-sensitive mechanoreceptors in the proximal stomach may signal discomfort and pain in case of impaired GA [13]. In addition, redistribution of the meal to the antrum may also contribute to symptom generation. Salet et al. [15] compared the gastric distribution of food in healthy volunteers and FD patients. During these experiments, decreased GA in FD patients was associated with a rapid redistribution of the ingested content to the distal stomach. Similar results were obtained earlier by Troncon et al. [31] using scintigraphy, which also showed redistribution of food to the antrum in FD. In line with these studies, Caldarella et al. [32] showed that both the proximal stomach and the antrum are hypersensitive to distention in FD patients compared to healthy subjects. Hence, when impaired GA leads to antral volume overload, this is highly likely to provoke symptoms in FD patients.
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
Visceral Hypersensitivity
225
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
Visceral sensation can be determined by means of transmission of chemical and mechanical sensing. Conceptually, the gastric wall contains two types of mechanoreceptors: mechanoreceptors arranged in parallel to the smooth muscle that respond to elongation, and mechanoreceptors arranged in series to the smooth muscle that respond to wall tension [13, 48]. Chemosensitive modalities are multiple and varied, including nutrient sensing, acid sensitivity, taste sensing, etc. [33]. Signals from the mechano- and chemoreceptors travel from the gut in a 3-neuron-chain to the central nervous system [48]. The first-order neuron, with cell body in the dorsal root ganglia, travels via an afferent pathway from the gut to the spinal cord. Here, signals ascend via the secondorder neuron to the thalamus and brain through the spinothalamic and spinoreticular tracts and synapse with the autonomic and satiety centers. Finally, the limbic system (emotional responses) and the sensory cortex (conscious perception) are reached by the third-order neuron [48]. Gastric mechanosensitivity is studied by balloon distention using the gastric barostat, which allows delivering stepwise isobaric or isovolumetric increments of the gastric balloon in the stomach in the fasted state. Both pressure and volume of the balloon influence sensitivity to gastric distention [49]. Hence, it has been suggested that gastric wall tension during the gastric distention is the sensory modality leading to perception [48–50]. Gastric
wall tension during balloon distention can be estimated by using the law of Laplace, and application of this formula supports the hypothesis that insufficient GA to a meal increases intragastric wall tension [48–50]. However, applying this formula requires a number of assumptions that are not necessarily fulfilled: the stomach has a perfect spherical shape, the gastric wall is infinitely thin, and no active contractile activity occurs [48]. By means of the gastric barostat, the gastric compliance can also be studied. The gastric compliance is defined as the relation between stepwise isobaric pressures and the corresponding intraballoon volume [48]. It has been shown in a number of studies that a subgroup of FD patients are hypersensitive to balloon distention, in spite of normal compliance (fig. 1) [49–52]. Hypersensitivity to gastric distention is defined as a decrease in the first perception threshold and the discomfort threshold below the normal range in healthy volunteers [51]. In the largest cohort study to date, hypersensitivity to distention in FD was associated with symptoms of postprandial pain, excessive belching and unexplained weight loss [51]. In keeping with a role for tension receptors, drugs that decrease gastric wall tension, such as sumatriptan and clonidine, decrease sensitivity to gastric distention and decrease the severity of meal-induced dyspeptic symptoms [50]. The majority of FD patients reported that symptoms were triggered or aggravated after the meal [53]. Therefore, it has been suggested that postprandial hypersensitivity might be most relevant to the generation of FD symptoms. However, there is a large number of variables that may affect gastric sensitivity after a meal, such as GA, gastric acid secretion, duodenal acid exposure, altered gastroduodenal hormone secretion, and the nutrient composition of the meal [11, 33, 52–56]. In a recent study, Farré et al. [56] studied the sensitivity to distention after a meal in FD patients and compared it to healthy volunteers. The study showed that in FD after a meal the gastric sensitivity to distention is enhanced and is significantly correlated to the cumulative meal-related dyspeptic symptom score. This implies that postprandial sensitivity to gastric distention, which depended on both hypersensitivity in the fasting state and GA, is an important contributor to symptom generation in FD. The other modality that has been extensively studied in FD is visceral chemosensitivity. Capsaicin, the natural compound of chili pepper, is an agonist at the transient receptor potential type 1 (TRP1) channel which converts thermal and chemical stimuli into painful sensations or discomfort [57–59]. Moreover, it has been previously ob-
emptying or idiopathic gastroparesis, and other mechanisms such as impaired accommodation and visceral hypersensitivity are important factors driving symptom pattern and severity [46]. Idiopathic gastroparesis and diabetic gastroparesis are usually managed by prokinetic drugs, assuming that acceleration of the gastric emptying will ameliorate the symptoms. Data from a recent systematic analysis show that the use of prokinetic drugs such as metoclopramide, domperidone, cisapride, erythromycin, and levosulpiride indeed improves symptoms and gastric emptying in gastroparesis patients, but none of these drugs showed a significant correlation between symptom improvement and the effect on gastric emptying [47]. This implies that improvement of the symptoms is not necessarily due to their effect on gastric emptying but also on other different factors such as an effect on GA or on gastric sensitivity, or central effects.
Low-Grade Inflammation and Mucosal Permeability
The mucosal barrier serves as the first line of defense against pathogens. The gastroduodenal mucosal barrier results from a complex interplay between extracellular and cellular components [66]. Between the cells, a combination of tight and adherens junction regulates and seals the paracellular space. These junctions are therefore the rate-limiting step in transepithelial transport and the principal determinant of mucosal permeability [67]. In IBS and IBD studies, it has been hypothesized that mucosal barrier dysfunction could facilitate the passage of luminal antigens and elicit an immune response. This response could cause a low-grade inflammation that generates IBS symptoms [6, 68]. This hypothesis has also been 226
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
taken into account for the study of underlying mechanisms in FD [8]. H. pylori has long been suggested to be one of the pathogenetic factors in FD [69–72]. At present, studies have shown that H. pylori plays an important role in damaging the integrity of the gastric epithelial barrier [73, 74]. However, the role of H. pylori in FD remains unestablished, based on the lack of association of H. pylori presence with symptom pattern and gastric sensorimotor function, and the limited and late-onset response to eradication therapy [6, 69, 72]. Other pathogenic organisms may also be relevant to FD pathogenesis: it has been previously observed that gastric infections other than H. pylori increase the prevalence of FD [75–77]. A study from Leuven showed that FD patients that had a history suggestive of postinfectious dyspepsia showed prevalent symptoms of early satiety, weight loss, nausea and vomiting compared to unspecified-onset FD [77]. Moreover, impaired GA was also more prevalent in this group, and this was attributable to a defect at the level of gastric intrinsic nitrergic neurons [77]. Kindt et al. [78] found that this group of patients with postinfectious FD showed signs of activation of duodenal immune cells. The results of duodenal biopsies of postinfectious FD patients showed focal aggregates of CD8+ T cells, a decrease in CD4+ and an increase in macrophages surrounding the crypts. Moreover, postinfectious FD patients showed delayed gastric emptying compared to unspecified-onset FD [78]. Other studies have also shown an increase in macrophages and eosinophils in the duodenal mucosa in FD, suggesting the presence of low-grade inflammation (fig. 1) [79–81]. Li et al. [81] reported low-grade inflammation in patients with postinfectious and unspecifiedonset FD. In gastric mucosal biopsy samples, the authors found increased numbers of mast cells in close proximity to nerves, and augmented expression of histamine, serotonin and tryptase compared with healthy controls. In postinfectious FD biopsies, the release of histamine and serotonin was higher, and the distance of mast cells to nerves was shorter than in unspecified FD [81]. Recent studies have addressed duodenal mucosal integrity in FD. Vanheel et al. [82] reported impaired mucosal barrier function and low-grade inflammation in the duodenum in FD patients (fig. 1). FD patients are characterized by the increased infiltration of mucosal mast cells and eosinophils in the mucosa, and this is correlated with altered expression of certain cell-to-cell adhesion proteins such as occludin and zonulin-1, β-catenin, Ecadherin and desmoglein-2. Although these data show a Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
served that the TRP1 channel could also be involved in gastric motility regulation. Studies with capsaicin in FD patients showed an increase in hypersensitivity and dyspeptic upper gut symptoms [57–61]. However, the known hypersensitivity in the subjects was not a predictor for the symptoms and their intensity [57]. Acid-suppressive therapy is a frequently used treatment modality in FD patients. Acid sensitivity in the stomach and duodenum has also been implicated in FD symptom generation. Oshima et al. [62] studied the effect of acid and water infusion in the stomach of FD patients and healthy subjects. The results showed that FD patients were more sensitive to the acid infusion compared to healthy volunteers, and they reported an increase in the quantity and severity of dyspeptic symptoms compared to water infusion. Studies using duodenal acid infusion in FD reported a reduced duodenal acid clearance and hypersensitivity to duodenal acid in patients, the most prominently induced dyspeptic symptom being nausea [55, 63, 64]. A study in FD patients with prominent nausea showed that patients had an increased endogenous acid exposure during daytime with reduced duodenal clearance [55]. It was also observed that the severity of the symptoms was related to the increased endogenous acid exposure. However, infusion of exogenous acid in the duodenum did not aggravate the symptoms. Prolonged duodenal acid infusion in healthy subjects induces dyspeptic symptoms such discomfort, bloating, nausea and epigastric burning [65]. Finally, it has also been shown that after infusion of exogenous acid in the duodenum the threshold for discomfort to gastric balloon distention decreased [54]. Moreover, the GA to a meal decreased after acid exposure compared to saline.
clear relation between mucosal permeability and lowgrade inflammation, a causal relationship in either direction remains to be established [82]. Most recently, Vanuytsel et al. [83] studied the impact of acute psychological stress on duodenal mucosal integrity in a group of healthy volunteers. The authors showed that stress-induced activation of the hypothalamo-pituitary-adrenal axis increased duodenal mucosal permeability and that this effect was dependent on mast cell activation. The effect of stress-induced hyperpermeability could be mimicked by exogenous administration of corticotropin-releasing hormone (CRH), and both stress-induced and CRH-induced hyperpermeability could be suppressed by previous mast cell stabilization [83]. The role of stress and mast cells in FD patients with increased duodenal permeability remains to be studied.
Conclusion
FD is one of the most common gastrointestinal disorders encountered in clinical practice. From a pathophysiological viewpoint, FD is a heterogeneous disorder in which different mechanisms are associated with different symptom profiles (fig. 1). Over the last years, the amount of knowledge regarding the pathophysiology of FD has increased tremendously. However, at the same time, a number of new hypotheses and questions were raised by this research. It is conceivable that a better understanding of the underlying pathogenesis and symptom generation in FD may lead to the development of improved treatment options and better symptom control.
Disclosure Statement None.
References
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
10 Kindt S, Tack J: Impaired gastric accommodation and its role in dyspepsia. Gut 2006;55: 1685–1691. 11 Janssen P, Vanden Berghe P, Verschueren S, Lehmann A, Depoortere I, Tack J: Review article: the role of gastric motility in the control of food intake. Aliment Pharmacol Ther 2011; 33:880–894. 12 Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J: Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998;115:1346–1352. 13 Piessevaux H, Tack J, Wilmer A, Coulie B, Geubel A, Janssens J: Perception of changes in wall tension of the proximal stomach in humans. Gut 2001;49:203–208. 14 Paintal AS: A study of gastric stretch receptors; their role in the peripheral mechanism of satiation of hunger and thirst. J Physiol 1954; 126:255–270. 15 Salet GA, Samsom M, Roelofs JM, van Berge Henegouwen GP, Smout AJ, Akkermans LM: Responses to gastric distension in functional dyspepsia. Gut 1998;42:823–829. 16 Tack J, Demedts I, Meulemans A, Schuurkes J, Janssens J: Role of nitric oxide in the gastric accommodation reflex and in meal induced satiety in humans. Gut 2002;51:219–224. 17 Tonini M, De Giorgio R, De Ponti F, Sternini C, Spelta V, Dionigi P, et al: Role of nitric oxide- and vasoactive intestinal polypeptidecontaining neurones in human gastric fundus strip relaxations. Br J Pharmacol 2000; 129: 12–20.
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
18 Takahashi T, Owyang C: Vagal control of nitric oxide and vasoactive intestinal polypeptide release in the regulation of gastric relaxation in rat. J Physiol 1995;484:481–492. 19 Grover M, Camilleri M: Effects on gastrointestinal functions and symptoms of serotonergic psychoactive agents used in functional gastrointestinal diseases. J Gastroenterol 2013;48:177–181. 20 Gershon MD, Tack J: The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 2007;132:397–414. 21 Geeraerts B, Van Oudenhove L, Boesmans W, Vos R, Vanden Berghe P, Tack J: Influence of acute tryptophan depletion on gastric sensorimotor function in humans. Am J Physiol Gastrointest Liver Physiol 2011; 300:G228– G235. 22 Tack J, Broekaert D, Coulie B, Fischler B, Janssens J: Influence of the selective serotonin re-uptake inhibitor, paroxetine, on gastric sensorimotor function in humans. Aliment Pharmacol Ther 2003;17:603–608. 23 Tack J, Broeckaert D, Coulie B, Janssens J: The influence of cisapride on gastric tone and the perception of gastric distension. Aliment Pharmacol Ther 1998;12:761–766. 24 Tack J, Janssen P, Bisschops R, Vos R, Phillips T, Tougas G: Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia. Neurogastroenterol Motil 2011;23:e32–e39.
227
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
1 Tack J, Talley NJ, Camilleri M, Holtmann G, Hu P, Malagelada JR, et al: Functional gastroduodenal disorders. Gastroenterology 2006; 130:1466–1479. 2 Tack J, Talley NJ: Functional dyspepsia – symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013;10:134–141. 3 Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P: Effect of dyspepsia on survival: a longitudinal 10-year follow-up study. Am J Gastroenterol 2012;107:912–921. 4 El-Serag HB, Talley NJ: Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther 2003;18:387–393. 5 Moayyedi P, Mason J: Clinical and economic consequences of dyspepsia in the community. Gut 2002;50(suppl 4):iv10–iv12. 6 Tack J, Talley NJ: Functional dyspepsia – symptoms, definitions and validity of the Rome III criteria. Nat Rev Gastroenterol Hepatol 2013;10:134–141. 7 Talley NJ: Review article: functional dyspepsia – should treatment be targeted on disturbed physiology? Aliment Pharmacol Ther 1995;9:107–115. 8 Vanheel H, Farré R: Changes in gastrointestinal tract function and structure in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:142–149. 9 Van Oudenhove L, Aziz Q: The role of psychosocial factors and psychiatric disorders in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:158–167.
228
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
41 Lacy BE: Functional dyspepsia and gastroparesis: one disease or two? Am J Gastroenterol 2012;107:1615–1620. 42 Janssen P, van Oudenhove L, Bisschops R, Tack J: Idiopathic gastroparesis or functional dyspepsia with delayed gastric emptying: where is the difference? Gastroenterology 2011; 140: 2145–2146; author reply 2146– 2148. 43 Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J: Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003;98: 783–788. 44 Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, Marengo M, Corinaldesi R: Risk indicators of delayed gastric emptying of solids in patients with functional dyspepsia. Gastroenterology 1996;110:1036–1042. 45 Talley NJ, Locke GR 3rd, Lahr BD, Zinsmeister AR, Tougas G, Ligozio G, Rojavin MA, Tack J: Functional dyspepsia, delayed gastric emptying, and impaired quality of life. Gut 2006;55:933–939. 46 Karamanolis G, Caenepeel P, Arts J, Tack J: Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction? Gut 2007;56:29–36. 47 Janssen P, Harris MS, Jones M, Masaoka T, Farre R, Tornblom H, et al: The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis. Am J Gastroenterol 2013;108:1382–1391. 48 Camilleri M, Coulie B, Tack JF: Visceral hypersensitivity: facts, speculations, and challenges. Gut 2001;48:125–131. 49 Notivol R, Coffin B, Azpiroz F, Mearin F, Serra J, Malagelada JR: Gastric tone determines the sensitivity of the stomach to distention. Gastroenterology 1995;108:330–336. 50 Tack J, Caenepeel P, Corsetti M, Janssens J: Role of tension receptors in dyspeptic patients with hypersensitivity to gastric distention. Gastroenterology 2004;127:1058–1066. 51 Mertz H, Fullerton S, Naliboff B, Mayer EA: Symptoms and visceral perception in severe functional and organic dyspepsia. Gut 1998; 42:814–822. 52 Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J: Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121: 526– 535. 53 Bisschops R, Karamanolis G, Arts J, Caenepeel P, Verbeke K, Janssens J, Tack J: Relationship between symptoms and ingestion of a meal in functional dyspepsia. Gut 2008; 57: 1495–1503. 54 Lee KJ, Vos R, Janssens J, Tack J: Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol 2004; 286:G278–G284.
55 Lee KJ, Demarchi B, Demedts I, Sifrim D, Raeymaekers P, Tack J: A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am J Gastroenterol 2004; 99:1765–1773. 56 Farré R, Vanheel H, Vanuytsel T, Masaoka T, Tornblom H, Simren M, et al: In functional dyspepsia, hypersensitivity to postprandial distention correlates with meal-related symptom severity. Gastroenterology 2013; 145: 566–573. 57 Hammer J, Fuhrer M, Pipal L, Matiasek J: Hypersensitivity for capsaicin in patients with functional dyspepsia. Neurogastroenterol Motil 2008;20:125–133. 58 Holzer P: Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev 1991; 43: 143– 201. 59 Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 1997;389:816–824. 60 Anand P, Aziz Q, Willert R, van Oudenhove L: Peripheral and central mechanisms of visceral sensitization in man. Neurogastroenterol Motil 2007;19(suppl 1):29–46. 61 Fuhrer M, Vogelsang H, Hammer J: A placebo-controlled trial of an oral capsaicin load in patients with functional dyspepsia. Neurogastroenterol Motil 2011;23:918-e397. 62 Oshima T, Okugawa T, Tomita T, Sakurai J, Toyoshima F, Watari J, et al: Generation of dyspeptic symptoms by direct acid and water infusion into the stomachs of functional dyspepsia patients and healthy subjects. Aliment Pharmacol Ther 2012;35:175–182. 63 Schwartz MP, Samsom M, Smout AJ: Chemospecific alterations in duodenal perception and motor response in functional dyspepsia. Am J Gastroenterol 2001;96:2596–2602. 64 Samsom M, Verhagen MA, vanBerge Henegouwen GP, Smout AJ: Abnormal clearance of exogenous acid and increased acid sensitivity of the proximal duodenum in dyspeptic patients. Gastroenterology 1999; 116: 515– 520. 65 di Stefano M, Vos R, Vanuytsel T, Janssens J, Tack J: Prolonged duodenal acid perfusion and dyspeptic symptom occurrence in healthy volunteers. Neurogastroenterol Motil 2009; 21:712-e40. 66 Turner JR: Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 2009;9:799–809. 67 Ohman L, Simren M: Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol 2010;7:163–173. 68 Salim SY, Soderholm JD: Importance of disrupted intestinal barrier in inflammatory bowel diseases. Inflamm Bowel Dis 2011; 17: 362–381. 69 Suzuki H, Moayyedi P: Helicobacter pylori infection in functional dyspepsia. Nat Rev Gastroenterol Hepatol 2013;10:168–174.
Carbone/Tack
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
25 Tack J, Vos R, Janssens J, Salter J, Jauffret S, Vandeplassche G: Influence of tegaserod on proximal gastric tone and on the perception of gastric distension. Aliment Pharmacol Ther 2003;18:1031–1037. 26 Van Oudenhove L, Kindt S, Vos R, Coulie B, Tack J: Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther 2008;28:1326–1333. 27 Tack J, Janssen P, Masaoka T, Farre R, Van Oudenhove L: Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol 2012; 10:1239–1245. 28 Ameloot K, Janssen P, Scarpellini E, Vos R, Boesmans W, Depoortere I, et al: Endocannabinoid control of gastric sensorimotor function in man. Aliment Pharmacol Ther 2010;31:1123–1131. 29 Janssen P, Pottel H, Vos R, Tack J: Endogenously released opioids mediate meal-induced gastric relaxation via peripheral muopioid receptors. Aliment Pharmacol Ther 2011;33:607–614. 30 Carrasco M, Azpiroz F, Malagelada JR: Modulation of gastric accommodation by duodenal nutrients. World J Gastroenterol 2005;11: 4848–4851. 31 Troncon LE, Bennett RJ, Ahluwalia NK, Thompson DG: Abnormal intragastric distribution of food during gastric emptying in functional dyspepsia patients. Gut 1994; 35: 327–332. 32 Caldarella MP, Azpiroz F, Malagelada JR: Antro-fundic dysfunctions in functional dyspepsia. Gastroenterology 2003;124:1220–1229. 33 Farré R, Tack J: Food and symptom generation in functional gastrointestinal disorders: physiological aspects. Am J Gastroenterol 2013;108:698–706. 34 Bouras EP, Vazquez Roque MI, Aranda-Michel J: Gastroparesis: from concepts to management. Nutr Clin Pract 2013;28:437–447. 35 Parkman HP, Camilleri M, Farrugia G, McCallum RW, Bharucha AE, Mayer EA, et al: Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 2010;22:113–133. 36 Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L: Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013;108:18–37; quiz 38. 37 Masaoka T, Tack J: Gastroparesis: current concepts and management. Gut Liver 2009;3: 166–173. 38 Krishnan B, Babu S, Walker J, Walker AB, Pappachan JM: Gastrointestinal complications of diabetes mellitus. World J Diabetes 2013;4:51–63. 39 Choung RS, Locke GR 3rd, Schleck CD, Zinsmeister AR, Melton LJ 3rd, Talley NJ: Risk of gastroparesis in subjects with type 1 and 2 diabetes in the general population. Am J Gastroenterol 2012;107:82–88. 40 Hasler WL: Gastroparesis: pathogenesis, diagnosis and management. Nat Rev Gastroenterol Hepatol 2011;8:438–453.
Gastroduodenal Mechanisms Underlying Functional Gastric Disorders
75 Dizdar V, Gilja OH, Hausken T: Increased visceral sensitivity in Giardia-induced postinfectious irritable bowel syndrome and functional dyspepsia. Effect of the 5HT3-antagonist ondansetron. Neurogastroenterol Motil 2007;19:977–982. 76 Mearin F, Perez-Oliveras M, Perello A, Vinyet J, Ibanez A, Coderch J, et al: Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study. Gastroenterology 2005;129:98– 104. 77 Tack J, Demedts I, Dehondt G, Caenepeel P, Fischler B, Zandecki M, et al: Clinical and pathophysiological characteristics of acuteonset functional dyspepsia. Gastroenterology 2002;122:1738–1747. 78 Kindt S, Tertychnyy A, de Hertogh G, Geboes K, Tack J: Intestinal immune activation in presumed post-infectious functional dyspepsia. Neurogastroenterol Motil 2009; 21: 832e56. 79 Talley NJ, Walker MM, Aro P, Ronkainen J, Storskrubb T, Hindley LA, et al: Non-ulcer dyspepsia and duodenal eosinophilia: an adult endoscopic population-based case-control study. Clin Gastroenterol Hepatol 2007;5: 1175–1183.
Dig Dis 2014;32:222–229 DOI: 10.1159/000357854
80 Walker MM, Talley NJ, Prabhakar M, Pennaneac’h CJ, Aro P, Ronkainen J, et al: Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009;29:765–773. 81 Li X, Chen H, Lu H, Li W, Chen X, Peng Y, et al: The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia. Scand J Gastroenterol 2010; 45: 573–581. 82 Vanheel H, Vicario M, Vanuytsel T, Van Oudenhove L, Martinez C, Keita AV, et al: Impaired duodenal mucosal integrity and low-grade inflammation in functional dyspepsia. Gut 2013, Epub ahead of print. 83 Vanuytsel T, van Wanrooy S, Vanheel H, Vanormelingen C, Verschueren S, Houben E, et al: Psychological stress and corticotropinreleasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut 2013, Epub ahead of print.
229
Downloaded by: Universitätsbibliothek Giessen 134.176.129.147 - 5/12/2015 4:17:52 PM
70 Tucci A, Corinaldesi R, Stanghellini V, Tosetti C, Di Febo G, Paparo GF, et al: Helicobacter pylori infection and gastric function in patients with chronic idiopathic dyspepsia. Gastroenterology 1992;103:768–774. 71 Mearin F, de Ribot X, Balboa A, Salas A, Varas MJ, Cucala M, et al: Does Helicobacter pylori infection increase gastric sensitivity in functional dyspepsia? Gut 1995;37:47–51. 72 Sarnelli G, Cuomo R, Janssens J, Tack J: Symptom patterns and pathophysiological mechanisms in dyspeptic patients with and without Helicobacter pylori. Dig Dis Sci 2003; 48:2229–2236. 73 Wu J, Xu S, Zhu Y: Helicobacter pylori CagA: a critical destroyer of the gastric epithelial barrier. Dig Dis Sci 2013;58:1830–1837. 74 Fiorentino M, Ding H, Blanchard TG, Czinn SJ, Sztein MB, Fasano A: Helicobacter pyloriinduced disruption of monolayer permeability and proinflammatory cytokine secretion in polarized human gastric epithelial cells. Infect Immun 2013;81:876–883.
