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Abstract

Background

Although many patients with functional dyspepsia experience headache concurrently with dyspeptic symptoms, studies suggesting mechanisms underlying this phenomenon are limited. Herein, we explore the relationship between gastrointestinal inflammatory cells and presence of headache associated with dyspeptic symptoms in children with Helicobacter pylori-negative functional dyspepsia.

Methods

Fifty-six patients with H. pylori-negative functional dyspepsia underwent upper endoscopy with biopsy to investigate recurrent epigastric pain or discomfort. Patients were divided into two groups according to self-reported presence of headache associated with dyspeptic symptoms. Inflammatory cells including mast cells, and enteroendocrine cells in the gastroduodenal mucosa were evaluated. Associations between headache presence and cellular changes in the gastroduodenal mucosa were examined.

Results

Headache was not associated with the grade of lymphocytes, neutrophil infiltration, or enteroendocrine cell density in the gastroduedenal mucosa. However, headache was significantly associated with high mast cell density in the body (27.81 ± 8.71 vs. 20.30 ± 8.16, p < 0.01) and duodenum (23.16 ± 10.40 vs. 14.84 ± 5.88, p < 0.01).

Conclusions

Presence of headache associated with dyspeptic symptoms is strongly related to mucosal mast cell density in pediatric patients with H. pylori-negative functional dyspepsia. Thus, our results may help clinicians understand and treat headache during dyspeptic symptoms in such pediatric patients.

Keywords

Functional dyspepsia headache mast cells enteroendocrine cells

Introduction

Headache is frequently associated with functional gastrointestinal disorders (1,2). The association between chronic headache, migraine, and irritable bowel syndrome has been confirmed by several clinical observations and epidemiological studies (3,4). In a Danish study, the coincidence rate of irritable bowel syndrome and headache was found to be 60%, though this rate depended on the course of the syndrome (5). Although functional dyspepsia is a common gastrointestinal disorder in children (6), there has yet to be a similar study evaluating the relationship between functional dyspepsia and headache. However, we have encountered many patients with concurrent functional dyspepsia and headache in clinical practice, and a few studies have suggested possible common mechanisms underlying this phenomenon. Schurman et al. (7) examined the relationship between gastroduodenal mucosal inflammation and psychological functioning in pediatric patients with functional dyspepsia. They found a correlation between mast cell density and somatization and hypothesized that physical symptoms, like headache, in functional dyspeptic patients, result from mediators released by mast cells (7). Their hypothesis is attractive because increasing evidence suggests that mast cells play a role in generating dyspeptic symptoms as well as headache via mast cell-nerve interactions (8 –10). In addition, mast cells are of particular interest because they have been implicated as an important link between stress, gastrointestinal dysfunctions, and headache. Mast cells may thus explain the interaction between psychological and biological factors in the development and persistence of abdominal pain and headache (11,12).

However, it may be difficult to determine whether headache is directly correlated with mucosal mast cell density in pediatric patients with functional dyspepsia because headache was one of several symptoms of somatization in the study by Schurman et al. (7). According to their results, headache should occur simultaneously with dyspeptic symptoms, yet they did not mention such a concurrence in their study. Therefore, the present study aimed to explore the relationship between gastroduodenal inflammatory cells and presence of headache associated with dyspeptic symptoms in functional dyspepsia in children. Although our primary interest was mast cells, we also examined additional characteristics of general inflammation (i.e. neutrophils for acute inflammation and lymphocytes for chronic inflammation) and enteroendocrine cells (i.e. enterochromaffin cells, enterochromaffin-like cells, and G cells) to determine whether such a relationship is unique to mast cells. General inflammation in the gut is associated not only with gastrointestinal diseases including functional dyspepsia (13) but also with headache (14). Additionally, mast cells can recruit these circulating inflammatory cells to the gastric mucosa (15). Most histamine in the body is synthesized by mast cells, and histamine has been suggested to play a key role in generating dyspeptic symptoms and headache (8 –10). However, enteroendocrine cells also synthesize important signaling molecules that link the brain and gut, including most of the body’s serotonin and some histamine (16). Therefore, it was impossible to determine which cells were directly related to functional dyspepsia or headache if nonspecific general inflammation or enteroendocrine cells was combined with mast cell infiltration. We excluded functional dyspeptic patients with Helicobacter pylori infection in order to avoid the extragastric effects of these bacteria.

Methods

Patients

Seventy-four consecutive school-age children (range six to 12 years) underwent endoscopy to investigate recurrent epigastric pain or discomfort and were diagnosed with functional dyspepsia at the Department of Pediatrics of Gyeongsang National University Hospital from August 1996 to December 2002. Diagnosis was made according to the Rome III pediatric criteria (17). Eighteen patients were excluded because of H. pylori infection. The remaining patients were divided into two groups, a headache-positive (+) group and a headache-negative (−) group, according to the self-reported presence or absence of headache-associated dyspeptic symptoms. This study was approved by the Gyeongsang National University Hospital Institutional Review Board (GNUHIRB-2011-107).

Gastroduodenal inflammation

Inflammatory cells, neuroendocrine cells, and H. pylori were measured in mucosal biopsy specimens obtained by endoscopy. Two biopsy specimens each were taken from the gastric antrum, body, and duodenal mucosa. The biopsy specimens obtained from the antrum and body were inoculated in 1% urea broth. The urease test was considered positive when the urea broth at 37°C showed a color change from yellow to pink within 48 hours. Specimens were stained with hematoxylin and eosin in the standard fashion to detect H. pylori and for general inflammation grading. We excluded patients if H. pylori was detected by urease test or histopathologic analysis of any specimen. To grade the acute and chronic inflammation of gastroduodenum, neutrophil and lymphocyte infiltration was conducted according to the Sydney system: grade 0, absent; grade 1, mild; grade 2, moderate; and grade 3, severe.

Mast cells were enumerated using immunohistochemical techniques. Paraffin-embedded blocks were sectioned at 5 µm thickness, and the endogenous peroxidase activity was inhibited by treating the sections with 0.5% periodic acid for 30 min. The specimens were incubated for 20 hours at 4°C with 1:500 diluted mouse anti-human mast cell tryptase Ab (Dako, Carpinteria, CA, USA). They were then washed three times with 0.05 M phosphate-buffered saline (PBS) for 10 min and incubated with biotinylated goat anti-mouse IgG (Dako) for 90 min. Next, the specimens were incubated with streptavidin (Dako) for one hour. They were then washed and stained with 0.025% 3,3′-diaminobenzidine tetrahydrochloride. To evaluate enteroendocrine cells, Grimelius silver staining was performed. Afterward the specimens were reacted with silver solution (30 mg silver nitrate, 90 ml distilled water (DW), and 10 ml 0.1 M pH 5.6 acetate buffer) at 60°C for four hours. We reduced the specimen for one min with Bodian reducing solution (1 g hydroquinone, 5 g sodium sulfite, and 100 ml DW) that had been previously warmed to 60°C and then counterstained with light green solution for 1 min.

After scanning tissue sections at low magnification (100×) to identify the most involved areas, tryptase-positive mast cells and enterochromaffin-like cells were counted in the lamina propria and epithelium in five consecutive non-overlapping fields at high power (400×) using Image J. Average cell counts were determined and expressed as the number of cells per high power field.

Statistical analysis

All statistical analyses were performed using SPSS version 12 (SPSS Inc., Chicago, IL). Fisher’s exact test, Student’s t test, and Mann-Whitney U test were used to examine the association between headache and both inflammatory cell density and grading. All p values were two tailed; an α level of <0.05 was considered statistically significant. We reported all p values without adjustment.

Results

Of the 56 H. pylori negative patients with functional dyspepsia, 32 were headache (+) and 24 were headache (−). Between the headache (+) and (−) groups, gender (69% and 63% female, respectively) and age (8.71 ± 1.61 and 8.72 ± 1.51 years, respectively) were not significantly different (p = 0.75 and p = 0.82, respectively). No relationship was found between the presence of headache and the grade of lymphocytes or neutrophil infiltration in the gastric antrum, body, or duodenum (Figure 1). In addition, no relationship was found between enteroendocrine cell density and headache (Figure 2). In the headache (+) and (−) groups, the presence of headache was significantly associated with high mast cell density in the gastric body (27.81 ± 8.71 vs. 20.30 ± 8.16, respectively, p < 0.01) and duodenum (23.16 ± 10.40 vs. 14.84 ± 5.88, respectively, p < 0.01) (Figure 2). No significant difference between the two groups was found in terms of the mast cell density in the antrum (22.97 ± 6.20 vs. 20.11 ± 7.99, p = 0.18) (Figure 2).

Figure 1.

Presence/absence of headache during dyspeptic symptoms in Helicobacter pylori-negative functional dyspepsia: Association with lymphocyte and neutrophil infiltration in gastroduodenal mucosa. HA (+): headache positive; HA (−): headache negative.

Figure 2.

Presence/absence of headache during dyspeptic symptoms in Helicobacter pylori-negative functional dyspepsia: Association with mast cell and enteroendocrine cell infiltration in gastroduodenal mucosa. HA (+): headache positive; HA (−): headache negative.

Discussion

In the present study, we showed that the occurrence of headache during dyspepsia was not related to acute or chronic inflammation, or enteroendocrine cell density in the gastroduodenal mucosa in pediatric functional dyspepsia patients. On the other hand, mast cell densities in the gastric body and duodenum were significantly higher in the presence of headache. Although Schurman et al. (7) also suggested that mast cell density and headache are correlated in pediatric patients with dyspepsia, it is difficult to interpret whether headache was directly correlated with mucosal mast cell density in that study, as mentioned in the introduction (i.e. there was no study of headache itself and no mention of the concurrence of headache). By contrast, our results clearly show that the presence of headache associated with dyspeptic symptoms was strongly related to the mucosal mast cell density in pediatric functional dyspeptic patients.

Mast cells have received considerable focus in the study of functional gastrointestinal disorders, such as functional dyspepsia (9,18,19), and in primary headaches, such as migraines (20). These cells may link symptoms from disparate anatomical locations (i.e. the brain and gastrointestinal tract) for several reasons. First, stress activates the hypothalamic-pituitary-adrenal axis by causing secretion of corticotrophin-releasing-factor (CRF), which can promote inflammation and nociceptor activation via mast cell degranulation (12). CRF-mediated mast cell degranulation or activation has been suggested to be an important mechanism of migraine and functional gastrointestinal disorders, which characteristically worsen or are precipitated by stress (12). An animal study showed that immobilization stress stimulates CRF release and causes degranulation in 70% of rat dura mast cells within 30 minutes (21). Complete inhibition of degranulation was achieved by pretreating animals with polyclonical antiserum to CRF (21). Similar studies in animal models of irritable bowel syndrome have also demonstrated that acute stress induces gastrointestinal functional disturbances through a pathway involving CRF and colonic mast cell activation (22,23). The role of stress in the pathogenesis and clinical presentation of symptoms has been most extensively studied in irritable bowel syndrome, but no study has investigated the role of CRF and stress in functional dyspepsia. However, delayed gastric emptying, one of the important signs of functional dyspepsia, is associated with stress (24) and mast cell density in the stomach (9). In addition, human observational studies have also suggested that stress and other psychological factors are related to functional dyspepsia and headache (25,26). Therefore, stress-induced mast cell activation via CRF may explain the interaction between psychological and biological factors in the concurrent development of functional dyspepsia and headache. Second, histamine and other mast cell mediators play a role in functional dyspepsia (19) and headache (27). Several studies have shown increased mast cell density in patients with functional dyspepsia (8,9,18), and mast cells may potentially produce dyspeptic symptoms because of mediator-induced alterations in gastric emptying or electrical rhythm (8). Additionally, histamine-rich foods, such as wine and cheese, are well known common triggers of food-related headache or migraine. Human studies with continuous infusion of histamine have shown that headache occurs during histamine infusion (27,28), which is followed by delayed headache with migraine characteristics (28). These findings suggest that headache can be triggered by circulating mediators from degranulated mast cells, particularly histamine. Quantitatively, histamine is a major inflammatory mediator released during mast cell degranulation. These mast cell mediators increase neuronal excitability and sensitivity, reciprocally activating mast cells leading to further release of neurotransmitters or neuropeptides (19). This positive feedback circuit produces hypersensitivity of the nerve and is one of the main pathophysiological mechanisms underlying functional dyspepsia and primary headache (12,29,30). Finally, a functional interaction between mast cells and nerves is supported by the close proximity of mast cells to nociceptor terminals in the meninges and to nerve fibers in the mucosal layer of the gastrointestinal tract (12). Therefore, the hypothetical scenario of a possible functional linkage between the brain and gut in pediatric functional dyspepsia can be summarized as follows: Stress may activate mast cells via CRF release, and mediators from mast cells have either a direct or indirect role in headache and dyspepsia.

Gastric distension might also link dyspeptic symptoms and headache via mast cell activation. Pucci et al. (2) found that the discomfort threshold after a meal was lower in functional dyspepsia patients with headache than in healthy volunteers and functional dyspepsia patients without headache. They suggested that the hypersensitivity to gastric distension is characteristic of not only functional dyspepsia but also migraine. However, they did not investigate underlying mechanisms to explain their findings. Hou et al. (8) suggested the possible involvement of mast cells in impaired gastric sensation in patients with functional dyspepsia in a dynamic human study. They compared proximal gastric sensation threshold between unselected patients with functional dyspepsia and healthy volunteers (8). The proximal gastric mucosa was biopsied under endoscopy before and after gastric distension, and the biopsied specimens were immunocytochemically stained using antihuman tryptase monoclonal antibody to evaluate mast cells. They found that patients with functional dyspepsia had a significantly lower threshold to proximal gastric distension than did the controls (8). Additionally, they showed that gastric hypersensitivity in patients with functional dyspepsia was associated with both an elevated number of mast cells in the gastric mucosa and increased degranulation of mast cells after gastric distension (8). Based on the findings of Pucci et al. and Hou et al., we suggest another hypothesis of a possible functional linkage between the brain and gut in pediatric functional dyspepsia: Histamine and other mediators resulting from mast cell degranulation after gastric distension induce not only dyspeptic symptoms but also headache, with severity proportional to the mediator level. However, Hou et al. (8) interpreted decreased mast cell number after gastric distension as mast cell degranulation, which does not confirm mast cell degranulation. Immunohistochemical analysis using mast cell tryptase alone does not specifically stain for degranulated mast cells but reflects the total number of mast cells including intact mast cells. Moreover, if the interpretation of Hou et al. is valid, we might be confronted with significant problems in drawing these conclusions from our results because we could not obtain information on the timing of the biopsies (whether patients were having symptoms or not at the time of biopsy). According to Hou et al., mast cell density would be lower in the headache (+) group than that in the headache (−) group if patients had dyspepsia or headache symptoms at the time of biopsy. Therefore, to test our hypotheses, further work is necessary to confirm mast cell degranulation by staining biopsied specimens metachromatically with acidified Toluidine blue. Additionally, the relationship between changes in histamine levels and headache occurrence after gastric distension or the correlation between symptom status at the time of biopsy and markers for mast cell activity in patients with functional dyspepsia should be evaluated.

Our results demonstrated that the role of mast cells in headache was independent of general inflammation and enteroendocrine cell infiltration. Like mast cells, enterochromaffin-like cells in the gastroduodenum can synthesize histamine (16). However, serotonin is a major mediator produced by enteroendocrine cells (most of the body’s serotonin is synthesized by enterochromaffin cells and enterochromaffin-like cells), and it activates intrinsic and extrinsic primary afferent neurons to initiate peristaltic and secretory reflexes (17). It is widely known that enteroendocrine cells are strongly associated with functional gastrointestinal disorders, especially irritable bowel syndrome (17). However, the roles of enteroendocrine cells and serotonin in functional dyspepsia are controversial. A recent study evaluating serotonin signaling in functional gastrointestinal disorders in pediatric patients suggested that enterochromaffin cells and serotonin signaling are altered in irritable bowel syndrome but not in functional dyspepsia (31). Unlike with mast cells, the response to stress is not clear for enteroendocrine cells. Kim et al. (22) showed that stress-mediated release of CRF may play a role in increasing mast cell count in functional gastrointestinal disorders, but not the number of enterochromaffin cells. Although it is known that serotonin is strongly associated with headache (32), enteroendocrine cell counts were not different between the patients with and without headache in our study. This finding may be a result of our study design, specifically because we excluded patients with H. pylori. Increased gastrin release has been observed in H. pylori-infected patients (33), and gastric enterochromaffin-like cell density is proportional to the level of gastrin secretion (16). Gastrin also stimulates enterochromaffin-like cells to release histamine (16). This suggests that H. pylori infection and headache may possibly be related to enteroendocrine cells in the gastroduodenal mucosa. Therefore, further studies are needed to evaluate the relationship between H. pylori and enteroendocrine cells in dyspeptic headache patients.

Our study has several strengths and limitations. To the best of our knowledge, our study is the first to attempt to show how inflammation in the gastroduodenal mucosa is related to headache in children with functional dyspepsia. In addition, we were able to obtain consistent information on the association of self-reported headache with dyspeptic symptoms because the same gastroenterology specialist took the histories of all of the patients included in this study, and asked the question in a standard way. Nevertheless, we could not determine detailed concurrent characteristics between headache and dyspeptic symptoms (whether headache occurred 100% concurrently with dyspepsia in individual cases, or whether headache persisted during dyspeptic symptoms), because standardized questionnaires were not used to assess concurrence of headache. Therefore, we used the terms “self-reported headache associated with dyspeptic symptoms” instead of “concurrence” of headache with dyspeptic symptoms. Furthermore, determining only the presence or absence of headache associated with dyspeptic symptoms does not provide a diagnostic assessment for headache. Because there are diverse subtypes of headaches with various underlying mechanisms, clarifying the headache characteristics may be important in explaining how inflammation in the gastroduodenal mucosa is related to headache. However, we did not classify headache subtype or measure severity or frequency. Most of the problems mentioned above might have originated from the limitations of a retrospective study. Therefore, further work with prospective assessment via a daily diary would be a more convincing strategy to demonstrate the concurrence and remediate the limitations associated with a retrospective self-report. In spite of this, grouping according to presence of headache associated with dyspeptic symptoms, which has never been done before, may be a more reasonable approach for linking these symptoms with histological inflammation in the gastroduodenal mucosa.

In conclusion, the present study provides preliminary evidence for a relationship between the occurrence of headache and cellular changes in the gastroduodenal mucosa in children with functional dyspepsia without H. pylori infection. The observed association between headache and gastroduodenal mast cell density may further elucidate the understanding of how the brain and gastrointestinal tract are functionally linked. Furthermore, our results may lead to improvements in clinical practice, as gastroenterologists may take an interest in neurological symptoms of functional dyspepsia (or vice versa) and prescribe specific drugs (such as mast cell stabilizers or antihistamines) to treat headache in pediatric patients with functional dyspepsia.

Clinical implications

Presence of headache associated with dyspeptic symptoms is strongly related to gastric mucosal mast cell density in pediatric patients with H. pylori-negative functional dyspepsia.

Our results suggest that mast cells may functionally link between the brain and the gut in pediatric functional dyspepsia.

Our results may lead to improvements in clinical practice, as gastroenterologists may take an interest in neurological symptoms of functional dyspepsia (or vice versa) and prescribe specific drugs for mast cells to treat headache in pediatric patients with functional dyspepsia.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Acknowledgements

The biospecimens for this study were provided by the Gyeongsang National University Hospital, a member of the National Biobank of Korea, which is supported by the Ministry of Health and Welfare.

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Relationship between headache and mucosal mast cells in pediatric Helicobacter pylori -negative functional dyspepsia

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Patients

Gastroduodenal inflammation

Statistical analysis

Results

Discussion

Clinical implications

Footnotes

Funding

Conflict of interest

Acknowledgements

References