Chronic nausea is common in children, reported by 15.9% in a community sample [1]. For children who fulfill Rome III criteria for a pain-associated functional gastrointestinal disorder (FGID), the prevalence rate is even higher (36%) [1]. This makes sense, as nausea tends to be associated with other gastrointestinal symptoms, including worse abdominal pain [2]. In youth with functional abdominal pain, co-morbid nausea has been associated with more somatic complaints, greater psychological dysfunction, increased disability, and poorer prognosis, making this an important symptom to understand in its own right [2].
The observed relationships between abdominal pain and nausea would suggest at least some shared pathophysiology. One possible mechanism would be mucosal inflammation (e.g. mast cells, eosinophils) which has been implicated in functional dyspepsia (FD) and irritable bowel syndrome (IBS) but unstudied in relation to nausea. Mast cells have been extensively evaluated in adults with IBS. Results have demonstrated increased mast cell density in the colon, ileum, and duodenum with increased mast cell degranulation [3,4,5,6]. Further, the density of mast cells in close proximity to neurons correlates with pain frequency and intensity in adults with IBS [5]. Mast cells and eosinophils also have been implicated in FD [7]. A recent systematic review and meta-analysis of 37 studies concluded that FD is associated with increases in both mast cells and eosinophils in the antrum and duodenum [8]. Increased eosinophil and mast cell degranulation has been demonstrated in both adults and children with FD, further implicating these two cells in this condition [9,10,11,12].
Mast cells, in particular, would have the potential to increase nausea in patients with FD. Nausea is a common symptom in patients with mastocytosis or mast cell activation syndrome as mast cells release cytokines which can lead to nausea [13,14,15]. In patients with eosinophilic esophagitis, higher tryptase levels are associated with increased nausea frequency [16]. Furthermore, in youth with FD, increased mast cell density is associated with slower gastric emptying and increased gastric dysrhythmia [11]. Gastric dysrhythmia has been associated with nausea [17, 18].
Previous studies of nausea have assessed patients with FGIDs associated with abdominal pain as defined by Rome III criteria. The criteria have undergone some significant revisions in the most recent Rome IV criteria, particularly in how FD and IBS are defined. Previously, under Rome III, FD was defined as upper abdominal pain or discomfort unrelated to stools [19]. Under Rome IV, FD is defined by the presence of: 1) epigastric abdominal pain unrelated to stools; 2) early satiety; and/or, 3) postprandial fullness [20]. IBS is defined by the presence of pain related to a change in: 1) stool frequency; 2) stool consistency; or, 3) pain with stooling. Previously, Rome III criteria required two of these symptoms to be present, while Rome IV criteria only requires one of these symptoms to be present [19, 20]. Changes in criteria may be important in assessing associations between nausea and FGIDs. For example, Kovacic and colleagues evaluated children with abdominal pain and nausea to determine whether symptom profiles fulfilled Rome III FD criteria, and found that 87% met adult FD criteria while only 29% met pediatric criteria [21].. This is relevant because the Rome III adult FD criteria are akin to the Rome IV pediatric FD criteria. Thus, it is likely that the diagnosis rate and group composition of patients included in studies using Rome III versus Rome IV pediatric criteria is quite different and, consequently, earlier findings regarding the relationship between abdominal pain and nausea based on Rome III classification many not be generalizable moving forward.
The major aims of the current study were to assess: 1) the frequency of nausea in patients with FD and IBS, respectively, as defined by Rome IV criteria; and, 2) relationships between nausea and mucosal inflammation as defined by antral and duodenal eosinophil and mast cell densities. A secondary aim was to assess relationships between nausea and other gastrointestinal symptoms, non-gastrointestinal somatic symptoms, and psychological dysfunction. Understanding the relationship between nausea, the new Rome IV diagnostic criteria, and inflammation will be important in order to determine if Rome IV provides cleaner diagnostic categories as related to nausea and to evaluate whether nausea should be viewed as a treatment target separate from abdominal pain or if the two should be viewed as co-morbid conditions with shared inflammatory pathophysiology.