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Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
ORIGINAL ARTICLES Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related? Carlos Alberto Velasco-Benitez, MD1,2, Cara Axelrod, RD3, Lilibet Fernandez Valdes, MD3, and Miguel Saps, MD3 Objectives To evaluate the prevalence of orthostatic intolerance and joint hypermobility in schoolchildren with and without functional gastrointestinal disorders (FGIDs) and to assess autonomic nervous system dysfunction in children with FGIDs and joint hypermobility. Study design Schoolchildren (10-18 years) attending public schools from 3 Colombian cities (Cali, Palmira, and Bucaramanga) completed validated questionnaires for FGIDs and underwent testing for hypermobility and autonomic nervous system dysfunction. Heart rate and blood pressure were assessed in recumbency and upright position at regular intervals. The differences in characteristics between schoolchildren with and without FGIDs were compared with a t-test for continuous variables and with a Fisher exact test (2 2 contingency tables) for categorical variables. Results In total, 155 children with FGIDs were matched with 151 healthy controls. Children with FGIDs had historically significant greater frequency of 10 of 12 symptoms of orthostatic intolerance, no significant difference in any symptoms of orthostatic intolerance during recumbency, significantly greater frequency in 6 of 12 symptoms of orthostatic intolerance during orthostasis, trend toward statistical significance for orthostatic intolerance (P = .0509), and no significant difference in prevalence of orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). There was no significant difference in prevalence of orthostatic intolerance, OH, and POTS between those with joint hypermobility and those without. Conclusions Children with FGIDs have a greater prevalence of symptoms of orthostatic intolerance but were not more likely to have OH and POTS as compared with children without FGIDs. Children with joint hypermobility did not have a greater prevalence of orthostatic intolerance, OH, and POTS. (J Pediatr 2019;-:1-7).
F
unctional gastrointestinal disorders (FGIDs) represent a major health burden worldwide.1 Patients consulting for FGIDs at tertiary care centers frequently present with joint hypermobility2 and symptoms of autonomic nervous system (ANS) dysfunction3 that manifest as orthostatic intolerance. Common forms of orthostatic intolerance include orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS).4 Orthostatic intolerance is characterized by the development of somatic symptoms with upright posture that improve with recumbence. POTS represents a common form of chronic orthostatic intolerance. In children and adolescents, the diagnosis of POTS is made when a sustained and symptomatic increase in heart rate (HR) occurs in the upright position, without a decrease in blood pressure (BP). Children with orthostatic intolerance whose BP decreases when they are in an upright position are diagnosed as having OH.5 Patients seeking a consultation for FGIDs alone, and patients seeking a consultation for either ANS dysfunction and/or joint hypermobility, report similar comorbidities. These include anxiety, depression, chronic fatigue, headaches, and sleep problems.5 As the pathophysiology of FGIDs remains unclear,6 it is important to understand whether the comorbidities of FGIDs and ANS dysfunction are pathophysiologically linked, are due to chance, or result from the selection bias of complex patients who seek a consultation at tertiary care centers. Clarifying whether these are true associations could open the door to novel treatments for a group of gastrointestinal disorders with poor outcomes. We conducted a study to evaluate the prevalence of orthostatic intolerance and joint hypermobility in schoolchildren with and without FGIDs and to assess ANS dysfunction in children with FGIDs and joint hypermobility. We hypothesized that patients with FGIDs would be more likely to present with orthostatic intolerance and those with orthostatic intolerance would be more likely to have POTS, OH, and joint hypermobility.
ANS BP FGID HR OH POTS
Autonomic nervous system Blood pressure Functional gastrointestinal disorder Heart rate Orthostatic hypotension Postural orthostatic tachycardia syndrome
From the 1Department of Pediatrics, Universidad del Valle, Colombia; 2Program in Clinical Medicine and Public Health, University of Granada, Spain; 3University of Miami Miller School of Medicine, Miami, FL The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.009
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Methods Parents of schoolchildren between the ages of 10 and 18 years attending public schools from 3 Colombian cities (Cali [southwest region], Palmira [southwest region], and Bucaramanga [northeastern region]) were invited to participate in the study through informative letters that did not reveal the aims and hypothesis of the study. Children with a history of organic gastrointestinal or metabolic diseases, eating disorders, or those who had signs of dehydration after physical examination by physicians were excluded. Participants completed age-appropriate validated questionnaires to diagnose FGIDs according to the Rome IV criteria (Questionnaire on Pediatric Gastrointestinal Symptoms-IV).7 Children who met criteria for at least 1 FGID were matched with a healthy control from the same sex and age. Cases and controls completed questionnaires regarding symptoms commonly associated with orthostatic intolerance. Surveys included historical binary questions (yes/no) on the incidence of dizziness, nausea, headaches, tremors, blurred vision, vertigo, anxiety, near syncope and syncope, sweating, and palpitations triggered by standing in the 2 months before the investigation. All sign/symptoms were again assessed during the recumbent (10 minutes) and standing phase (2, 5, and 10 minutes) of the investigation. Baseline HR and BP measures were obtained at each interval using an automatic blood pressure monitor (Honsun SCIAN LD-582; Shanghai Honsun International Trade Co Ltd, Shanghai, China). Patient’s excess of joint mobility was evaluated with the Beighton score (bilateral hypermobility of the fifth fingers, thumbs, knees, and elbows, and the ability to place palms flat on the floor with knees straight). A mechanical goniometer (Goniometro Professional; MSD, Kenilworth, New Jersey) was used to assist with joint mobility measures. Testing was conducted in each school at a quiet, temperature-controlled, isolated room absent of distractions. Members of the research team were present throughout the study to help complete questionnaires and to observe and record any symptoms that developed during testing. Orthostatic intolerance was characterized by having ³1 symptoms upon standing, such as lightheadedness, palpitations, generalized weakness, blurred vision, exercise intolerance, and fatigue. OH was defined as a drop in BP within 2 minutes of standing up of at least 20 mm Hg systolic blood pressure or at least 10 mm Hg diastolic BP.8 POTS was defined as an increase of HR of at least 40 beats per minute during the time period of upright position (10 minutes) without a decrease of systolic BP ³20 mm Hg,5 in adolescents £18 years. Joint hypermobility was clinically defined by the presence of a Beighton score of at least 4 of 9.9 Statistical Analyses Age, sex, and the diagnosis of orthostatic intolerance, OH, and POTS were assessed and compared between the groups of children with and without FGIDs. FGIDs were categorized 2
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by disorders of nausea and vomiting, including cyclic vomiting syndrome, functional nausea and vomiting disorders, rumination syndrome, and aerophagia, and by functional abdominal pain disorders, including functional dyspepsia, irritable bowel syndrome, abdominal migraines, and functional abdominal pain—not otherwise specified, as well as functional defecation disorders, including functional constipation and functional nonretentive incontinence. Data were calculated as percentages, means (SD; 95% CI). The differences in characteristics between schoolchildren with and without FGIDs were compared with a t-test for continuous variables and with a Fisher exact test (2 2 contingency tables) for categorical variables. Univariate analysis and bivariate analysis were calculated. ORs were calculated. Statistical significance was set at P < .05. The study was approved by the institutional review board and Human Subjects Committee of Universidad del Valle of Cali, Colombia. All participating children and their parents provided written consent.
Results A total of 1630 schoolchildren completed the Questionnaire on Pediatric Gastrointestinal Symptoms-IV. Of these, 267 children met criteria for FGIDs (16.2%) according to Rome IV criteria and were invited to participate in the study. One-hundred fifty-five of 267 children agreed to proceed with the second step of the study and underwent testing (10-12 years old, n = 41; 13-18 years old, n = 114). The group of children with FGIDs were matched with 155 healthy controls of similar age and sex without FGIDs from the same schools. Both groups were balanced in terms of age and sex (Figure). Four children did not follow up for further testing and were excluded from the study. No subjects were excluded due to dehydration. A total of 306 children with an age range of 10-18 years (109 females, P = .129) were finally included in the study (Figure). The most prevalent FGID Rome IV diagnostic category was functional defecation disorders (61.94%), followed by functional abdominal pain disorders (21.29%) and functional nausea and vomiting disorders (16.77%) Five children in the group of functional nausea and vomiting had overlap with other FGIDs (Table I).
Relationship between FGIDs and Symptoms of Orthostatic Intolerance by History (2 Months) Of 12 characteristic features of orthostatic intolerance that were surveyed, children with FGIDs reported a significantly greater frequency of 10 of them. There was no significant difference in reported prevalence of dizziness and loss of consciousness (reported by only 6 children) between those with FGIDs and those without. When defecation disorders were removed from analysis, 5 symptoms lost significance (headache, tremulousness, feeling hot, vertigo, and sweatiness) (Table II). Velasco-Benitez et al
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ORIGINAL ARTICLES
S creen in g
I d e n ti fic a tio n
Table I. Diagnosis of FGIDs (Rome IV criteria) Disorders (N = 155)
School-children invited to participate (n=2153)
Completed the QPGS IV questionnaires (n=1630)
No FGIDs (n=1363)
E l i g i b il i t y
FGIDs (n=267)
Disorders of functional nausea and functional vomiting Cyclic vomiting syndrome Functional nausea and vomiting disorders Nausea Vomiting Rumination syndrome Aerophagia Functional abdominal pain disorders Functional dyspepsia Irritable bowel syndrome Abdominal migraines Functional abdominal pain Functional defecation disorders Functional constipation Functional nonretentive encopresis
33* (21.29) 9 (5.81) 7 (4.52) 1 (0.65) 6 (3.87) 5 (3.23) 5 (3.23) 33 (21.29) 21 (13.55) 3 (1.94) 7 (4.52) 2 (1.29) 96 (61.94) 94 (60.65) 2 (1.29)
*There was an overlap of 5 children with more than 1 disorder.
Agreed to participate (n=155) In c lu d e d
N (%)
Matched controls agreed to participate (n=155)
Controls withdrew (n=4)
Figure. Flow diagram of patient enrollment. QPGS IV, Questionnaire on Pediatric Gastrointestinal Symptoms-IV.
Relationship between FGIDs and Symptoms of Orthostatic Intolerance at Recumbency (10 Minutes) There was no significant difference in prevalence in any of the symptoms between those with FGIDs and those without FGIDs during recumbency, even when defecation disorders were removed from analysis (Table III). Relationship between FGIDs and Symptoms of Orthostatic Intolerance at Orthostasis (10 Minutes) Of 12 characteristic features of orthostatic intolerance that were surveyed, children with FGIDs reported a significant greater frequency of 6 of them during orthostasis. When defecation disorders were removed from analysis, all findings lost significance (Table IV; available at www.jpeds.com). Relationship between FGIDs and Orthostatic Intolerance, OH, and POTS One hundred six of 155 (68.4%) children with FGIDs had orthostatic intolerance (P = .0509), trending toward statistical significance. Overall, there was no significant difference in prevalence of OH and POTS between those with FGIDs and those without. Two of 155 (1.3%) children with FGIDs had OH (P = .6309), and 5 of 155 (3.2%) children with FGIDs had POTS (P = .1059). When defecation disorders were
removed from analysis, there was no significant difference in prevalence of orthostatic intolerance and POTS between those with FGIDs and those without (Table V; available at www.jpeds.com). Relationship between Joint Hypermobility and Orthostatic Intolerance, OH, and POTS Eighty-seven of 306 (28.4%) children met criteria for joint hypermobility. Of the 87 with joint hypermobility, 56 had orthostatic intolerance (64.4%) (P = .7672). Only 1 child had both joint hypermobility and OH (1.2%) (P = .6735). Similarly, only 1 child had both joint hypermobility and POTS (1.2%) (P = .5188). Overall, there was no significant difference in prevalence of orthostatic intolerance, OH, and POTS between those with joint hypermobility and those without, even when defecation disorders were removed from analysis (Table VI; available at www.jpeds.com).
Discussion There have been several studies investigating the association between FGIDs, orthostatic intolerance, and joint hypermobility. Those studies have shown a high prevalence of autonomic disorders and joint hypermobility in individuals with FGIDs.2,10-12 However, all those studies have been tertiary clinic based. We were unable to establish whether there was a true association between autonomic disorders and FGIDs in children or whether it was the product of selection bias among those who seek a consult in specialized clinics. This study evaluated the prevalence of POTS and OH at the community level in children with or without FGIDs. We hypothesized that patients with FGIDs and joint hypermobility would be more likely to present with orthostatic intolerance. We found that many children in the community have symptoms of orthostatic intolerance, and that children with FGIDs more frequently reported a history of orthostatic intolerance than those without FGIDs. Although the difference in findings does not portray a statistically significant difference, it shows a clear trend (P = .0509). When recumbent,
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
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Nausea and vomiting disorders
All FGIDs
Symptoms
Absent
Absent
Present
Absent
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
P
n = 33 (%)
n = 151 (%)
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
103 (66.4) 52 (33.6)
87 (57.6) 64 (42.4)
.070
16 (61.5) 10 (38.5)
87 (57.6) 64 (42.4)
.440
25 (75.8) 8 (24.2)
87 (57.6) 64 (42.4)
.039
62 (64.6) 34 (35.4)
87 (57.6) 64 (42.4)
.169
41 (69.5) 18 (30.5)
87 (57.6) 64 (42.4)
.076
52 (33.6) 103 (66.4)
27 (17.9) 124 (82.2)
.001
6 (23.1) 20 (76.9)
27 (17.9) 124 (82.1)
.348
12 (36.4) 21 (63.6)
27 (17.9) 124 (82.1)
.020
32 (33.3) 64 (66.7)
27 (17.9) 124 (82.2)
.005
20 (33.9) 39 (66.1)
27 (17.9) 124 (82.2)
.012
88 (56.8) 67 (42.2)
69 (45.7) 82 (54.3)
.034
9 (34.6) 17 (65.4)
69 (45.7) 82 (54.3)
.202
20 (60.6) 13 (39.4)
69 (45.7) 82 (54.3)
.087
57 (59.4) 39 (40.6)
69 (45.7) 82 (54.3)
.024
31 (52.5) 28 (47.5)
69 (45.7) 82 (54.3)
.230
32 (20.7) 123 (79.3)
18 (11.9) 133 (88.1)
.028
2 (7.7) 24 (92.3)
18 (11.9) 133 (88.1)
.408
9 (27.3) 24 (72.7)
18 (11.9) 133 (88.1)
.029
24 (25.0) 72 (75.0)
18 (11.9) 133 (88.1)
.007
8 (13.6) 51 (86.4)
18 (11.9) 133 (88.1)
.454
77 (49.7) 78 (50.3)
41 (27.2) 110 (72.8)
.000
8 (30.8) 18 (69.2)
41 (27.2) 110 (72.8)
.433
20 (60.6) 13 (39.4)
41 (27.2) 110 (72.8)
.000
49 (51.0) 47 (49.0)
41 (27.2) 110 (72.8)
.000
28 (47.5) 31 (52.5)
41 (27.2) 110 (72.8)
.004
56 (36.1) 99 (63.9)
40 (26.5) 111 (73.5)
.045
8 (30.8) 18 (69.2)
40 (26.5) 111 (73.5)
.406
16 (48.5) 17 (51.5)
40 (26.5) 111 (73.5)
.013
38 (39.6) 58 (60.4)
40 (26.5) 111 (73.5)
.022
18 (30.5) 41 (69.5)
40 (26.5) 111 (73.5)
.336
45 (29.0) 110 (71.0)
34 (22.5) 117 (877.5)
.000
6 (23.1) 20 (76.9)
34 (22.5) 117 (77.5)
.563
9 (27.3) 24 (72.7)
34 (22.5) 117 (77.5)
.352
32 (33.3) 64 (66.7)
34 (22.5) 117 (877.5)
.043
13 (22.0) 46 (78.0)
34 (22.5) 117 (877.5)
.549
48 (31.0) 107 (69.0)
28 (18.5) 123 (81.5)
.008
10 (38.5) 16 (61.5)
28 (18.5) 123 (81.5)
.026
13 (39.4) 20 (60.6)
28 (18.5) 123 (81.5)
.011
30 (31.3) 66 (68.7)
28 (18.5) 123 (81.5)
.017
18 (30.5) 41 (69.5)
28 (18.5) 123 (81.5)
.047
44 (28.4) 111 (71.6)
15 (9.9) 136 (90.1)
.000
5 (19.2) 21 (80.8)
15 (9.9) 136 (90.1)
.147
14 (42.4) 19 (57.6)
15 (9.9) 136 (90.1)
.000
30 (31.3) 66 (68.7)
15 (9.9) 136 (90.1)
.000
14 (23.7) 45 (76.3)
15 (9.9) 136 (90.1)
.011
51 (32.9) 104 (67.1)
35 (23.2) 116 (76.8)
.039
9 (34.6) 17 (65.4)
35 (23.2) 116 (76.8)
.158
15 (45.5) 18 (54.5)
35 (23.2) 116 (76.8)
.010
39 (40.6) 57 (59.4)
35 (23.2) 116 (76.8)
.003
12 (20.3) 47 (79.7)
35 (23.2) 116 (76.8)
.403
37 (23.9) 118 (76.1)
17 (11.3) 134 (88.7)
.003
6 (23.1) 20 (76.9)
17 (11.3) 134 (88.7)
.095
12 (36.4) 21 (63.6)
17 (11.3) 134 (88.7)
.001
24 (25.0) 72 (75.0)
17 (11.3) 134 (88.7)
.004
13 (22.0) 46 (78.0)
17 (11.3) 134 (88.7)
.040
3 (1.9) 152 (98.1)
3 (2.0) 148 (98.0)
.645
0 (0.0) 26 (100.0)
3 (2.0) 148 (98.0)
.619
1 (3.0) 32 (97.0)
3 (2.0) 148 (98.0)
.550
2 (2.1) 94 (97.9)
3 (2.0) 148 (98.0)
.645
1 (1.7) 58 (98.3)
3 (2.0) 148 (98.0)
.686
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Present
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Velasco-Benitez et al
Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative
Present
Abdominal pain disorders
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Table II. Symptoms of orthostatic intolerance by history (2 months)
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Nausea and vomiting disorders
All FGIDs
Symptoms Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative n/a, not available.
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
58 (37.4) 97 (62.6)
54 (35.8) 97 (64.2)
.428
9 (34.6) 17 (65.4)
15 (9.7) 140 (90.3)
13 (8.6) 138 (91.4)
.450
42 (27.3) 112 (72.7)
44 (29.1) 107 (70.9)
27 (17.4) 128 (82.6)
Abdominal pain disorders Present
Absent
P
n = 33 (%)
n = 151 (%)
54 (35.8) 97 (64.2)
.549
13 (39.4) 20 (60.6)
1 (3.9) 25 (96.1)
13 (8.6) 138 (91.4)
.358
.407
7 (26.9) 19 (73.1)
44 (29.1) 107 (70.9)
24 (15.9) 127 (84.1)
.419
2 (7.7) 24 (92.3)
22 (14.2) 133 (85.8)
26 (17.2) 125 (82.8)
.284
22 (14.2) 133 (85.8)
27 (17.9) 124 (82.1)
37 (23.9) 118 (76.1)
Nausea, vomiting, and abdominal pain disorders
Defecation disorders Present
Absent
Present
Absent
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
54 (35.8) 97 (64.2)
.419
44 (45.8) 52 (54.2)
54 (35.8) 97 (64.2)
.075
14 (23.7) 45 (76.3)
54 (35.8) 97 (64.2)
.064
2 (6.1) 31 (93.9)
13 (8.6) 138 (91.4)
.473
11 (11.5) 85 (88.5)
13 (8.6) 138 (91.4)
.300
4 (6.8) 55 (93.2)
13 (8.6) 138 (91.4)
.452
.511
12 (36.4) 21 (63.6)
44 (29.1) 107 (70.9)
.268
30 (31.6) 65 (68.4)
44 (29.1) 107 (70.9)
.395
12 (20.3) 47 (79.7)
44 (29.1) 107 (70.9)
.130
24 (15.9) 127 (84.1)
.221
8 (24.2) 25 (75.8)
24 (15.9) 127 (84.1)
.184
21 (21.9) 75 (78.1)
24 (15.9) 127 (84.1)
.154
6 (10.2) 53 (89.8)
24 (15.9) 127 (84.1)
.201
3 (11.5) 23 (88.5)
26 (17.2) 125 (82.8)
.346
7 (21.2) 26 (78.8)
26 (17.2) 125 (82.8)
.374
15 (15.6) 81 (84.4)
26 (17.2) 125 (82.8)
.443
7 (11.9) 52 (88.1)
26 (17.2) 125 (82.8)
.231
.235
4 (15.4) 22 (84.6)
27 (17.9) 124 (82.1)
.506
4 (12.1) 29 (87.9)
27 (17.9) 124 (82.1)
.303
12 (12.5) 84 (87.5)
27 (17.9) 124 (82.1)
.171
10 (17.0) 49 (83.0)
27 (17.9) 124 (82.1)
.525
27 (17.9) 124 (82.1)
.125
7 (26.9) 19 (73.1)
27 (17.9) 124 (82.1)
.205
10 (30.3) 23 (69.7)
27 (17.9) 124 (82.1)
.088
22 (22.9) 74 (77.1)
27 (17.9) 124 (82.1)
.210
15 (25.4) 44 (74.6)
27 (17.9) 124 (82.1)
.150
32 (20.7) 123 (79.3)
25 (16.6) 126 (83.4)
.220
6 (23.1) 20 (76.9)
25 (16.6) 126 (83.4)
.288
6 (18.2) 27 (81.8)
25 (16.6) 126 (83.4)
.497
21 (21.9) 75 (78.1)
25 (16.6) 126 (83.4)
.189
11 (18.6) 48 (81.4)
25 (16.6) 126 (83.4)
.430
19 (12.3) 136 (87.7)
14 (9.3) 137 (90.7)
.256
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
15 (15.6) 81 (84.4)
14 (9.3) 137 (90.7)
.096
4 (6.8) 55 (93.2)
14 (9.3) 137 (90.7)
.393
20 (12.9) 135 (87.1)
16 (10.6) 135 (89.4)
.327
3 (11.5) 23 (88.5)
16 (10.6) 135 (89.4)
.553
8 (24.2) 25 (75.8)
16 (10.6) 135 (89.4)
.040
11 (11.5) 85 (88.5)
16 (10.6) 135 (89.4)
.494
9 (15.3) 50 (84.7)
16 (10.6) 135 (89.4)
.238
22 (14.2) 133 (85.8)
16 (10.6) 135 (89.4)
.218
3 (11.5) 23 (88.5)
16 (10.6) 135 (89.4)
.553
5 (15.2) 28 (84.8)
16 (10.6) 135 (89.4)
.315
19 (19.8) 77 (80.2)
16 (10.6) 135 (89.4)
.035
3 (5.1) 56 (94.9)
16 (10.6) 135 (89.4)
.163
0 (0.0) 155 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 26 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 33 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 96 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 59 (100.0)
0 (0.0) 151 (100.0)
n/a
5
ORIGINAL ARTICLES
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
Table III. Symptoms of orthostatic intolerance at recumbency (10 minutes)
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there was no significant difference in the prevalence of somatic symptoms in those with and without FGIDs. However, upon orthostasis, children with FGIDs were significantly more likely to feel dizziness, vertigo, nausea, headaches, tremors, blurred vision, hot, sweatiness, and near faint than patients without FGIDs. The fact that the history of orthostatic intolerance was more likely to match the incidence of symptoms with orthostasis but not with recumbence suggests the presence of an ANS dysfunction in those with FGIDs. However, our study showed that very few children with FGIDs had OH (1.3%) and POTS (3.2%). This suggests that selection bias may explain the presence of a significant greater prevalence of OH and POTS in children with FGIDs seen in tertiary centers.11 Nevertheless, due to the low frequency of these disorders in our sample, we cannot exclude that our study was not powered to find a significant difference in OH and POTS between children with and without FGIDs. In fact, POTS was more common in children with FGIDs without reaching statistical significance. Another important finding of the current study is that the history of orthostatic intolerance and basic clinic-based testing may be a reliable tool to discriminate children who may need formal autonomic testing for POTS and OH. A thorough history and initial testing for symptoms of orthostatic intolerance, HR, and BP in clinic in recumbent and orthostatic position may be warranted before referring patients to autonomic medicine. Autonomic specialists are scarce and testing is costly and not readily available in all centers. Moreover, due to the high prevalence of symptoms of orthostatic intolerance in children with FGIDs, conducting tilt-table testing in all children with FGIDs who report symptoms of autonomic disorders would be an untenable burden for the healthcare system. Taken together, physicians should aim to treat orthostatic intolerance when clinically relevant and refer those who do not improve to an autonomic medicine specialist for formal diagnosis and management. Practitioners should then be aware of the various treatment modalities applied to the treatment of autonomic disorders, as some of them can be recommended as primary measures to improve the patient’s symptoms. These include increased salt intake and fluids, progressive exercise, compression stockings up to the waist, beta-adrenoreceptor blockers, and corticosteroids.13 Our study raises an important issue by suggesting that presence of laxity of connective tissue by themselves are not sufficient to cause FGIDs or autonomic dysfunction. Children with joint hypermobility were not more likely to experience FGIDs, orthostatic intolerance, OH, and POTS. Similar to our findings in the relationship between FGIDs and orthostatic intolerance, a large number of children with joint hypermobility had orthostatic intolerance (64.4%). However, only 1 child with joint hypermobility met the criteria for OH (1.2%), and 1 for POTS (1.2%). Among the strengths of our study were the presence of local physicians onsite for history and testing. The school setting allowed us to obtain data from community children without the 6
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selection bias inherent to consultation patterns. Some of the additional strengths of our study include the large sample size, the use of validated questionnaires to diagnose FGIDs, and a goniometer to measure joint hypermobility. Orthostatic intolerance and BP and HR were measured under control environment that included temperature and noise. Our study also has limitations. The lack of information on medical consultation does not allow us to compare our data with clinic data. Approximately 60% patients who screened positive for FGIDs agreed to be enrolled in the study for further testing of POTS and hypermobility. The 40% who did not agree to be tested could have skewed the results of the prevalence of both group of conditions. Although we found a relationship between FGIDs and some symptoms of orthostatic intolerance, the design of our study does not allow to explain this relation. Also, we cannot establish whether the severity of symptoms worsened with orthostasis, as our study did not have a symptom intensity scale. The lack of this scale is unfortunate. In retrospect, we should have included not only a binary questionnaire but also a severity questionnaire. In addition, we did not use a tilt test for diagnosing orthostatic intolerance, and although OH requires measures of BP at 3 minutes of standing, children were evaluated at 2 minutes and 10 minutes of standing instead. In conclusion, children with FGIDs were only found to have a greater prevalence of symptoms of orthostatic intolerance but were not more likely to have OH and POTS as compared with the children without FGIDs. Thus, it is unlikely that the high frequency of reports of orthostatic intolerance in children with FGIDs could just be the result of selection bias. Based on the high prevalence of orthostatic intolerance and infrequent diagnosis of POTS and OH, it could be reasoned that the diagnostic criteria for POTS and OH may be too strict and therefore unintentionally dismiss individuals who still have symptoms. Children with joint hypermobility also were not found to have a greater prevalence of orthostatic intolerance, OH, and POTS, as compared with the children without joint hypermobility. This study reinforces the paradigm of the multifactorial nature of underlying pathophysiology of FGIDs. Large multinational studies are needed confirm our findings. n Submitted for publication Aug 12, 2019; last revision received Oct 7, 2019; accepted Nov 7, 2019. Reprint requests: Miguel Saps, MD, 1601 NW 12th Ave, Suite 3005A, Miami, FL 33136. E-mail: [email protected]; [email protected]
References 1. Wu JC. Psychological co-morbidity in functional gastrointestinal disorders: epidemiology, mechanisms and management. J Neurogastroenterol Motil 2012;18:13-8. 2. Kovacic K, Chelimsky TC, Sood MR, Simpson P, Nugent M, Chelimsky G. Joint hypermobility: a common association with complex functional gastrointestinal disorders. J Pediatr 2014;165:973-8. 3. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr 2001;33:47-53.
Velasco-Benitez et al
- 2019 4. Sullivan SD, Hanauer J, Rowe PC, Barron DF, Darbari A, OlivaHemker M. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr 2005;40:425-8. 5. Stewart JM, Boris JR, Chelimsky G, Fischer PR, Fortunato JE, Grubb BP, et al. Pediatric disorders of orthostatic intolerance. Pediatrics 2018;141:e20171673. 6. Ferreira-Maia AP, Matijasevich A, Wang YP. Epidemiology of functional gastrointestinal disorders in infants and toddlers: a systematic review. World J Gastroenterol 2016;22:6547-58. 7. Zeevenhooven J, Koppen IJ, Benninga MA. The New Rome IV Criteria for functional gastrointestinal disorders in infants and toddlers. Pediatr Gastroenterol Hepatol Nutr 2017;20:1-13. 8. Shen W-K, Sheldon RS, Benditt DG, Cohen MI, Forman DE, Goldberger ZD, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017;136:e25-59.
ORIGINAL ARTICLES 9. Saps M, Blom PJJ, Velasco-Benitez CA, Benninga MA. Functional gastrointestinal disorders and joint hypermobility: a school-based study. J Pediatr Gastroenterol Nutr 2018;66:387-90. 10. Chelimsky G, Kovacic K, Nugent M, Mueller A, Simpson P, Chelimsky TC. Comorbid conditions do not differ in children and young adults with functional disorders with or without postural tachycardia syndrome. J Pediatr 2015;167:120-4. 11. Beckers AB, Keszthelyi D, Fikree A, Vork L, Masclee A, Farmer AD, et al. Gastrointestinal disorders in joint hypermobility syndrome/EhlersDanlos syndrome hypermobility type: a review for the gastroenterologist. Neurogastroenterol Motil 2017;29:e13013. 12. Fikree A, Aktar R, Morris JK, Grahame R, Knowles CH, Aziz Q. The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study. Neurogastroenterol Motil 2017;29. 13. Xu WR, Jin HF, Du JB. Pathogenesis and individualized treatment for postural tachycardia syndrome in children. Chin Med J 2016;129: 2241-5.
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
7
Nausea and vomiting disorders
All FGIDs
Symptoms
Absent
Absent
Present
Absent
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
P
n = 33 (%)
n = 151 (%)
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
48 (31.0) 107 (69.0)
24 (15.9) 127 (84.1)
.001
5 (19.2) 21 (80.8)
24 (15.9) 127 (84.1)
.427
12 (36.4) 21 (63.6)
24 (15.9) 127 (84.1)
.010
36 (37.5) 60 (62.5)
24 (15.9) 127 (84.1)
.000
12 (20.3) 47 (79.7)
24 (15.9) 127 (84.1)
.282
20 (12.9) 135 (87.1)
10 (6.6) 141 (93.4)
.048
3 (11.5) 23 (88.5)
10 (6.6) 141 (93.4)
.293
5 (15.2) 28 (84.8)
10 (6.6) 141 (93.4)
.106
15 (15.6) 81 (84.4)
10 (6.6) 141 (93.4)
.020
5 (8.5) 54 (91.5)
10 (6.6) 141 (93.4)
.418
48 (31.0) 107 (69.0)
33 (21.9) 118 (78.1)
.047
10 (38.5) 16 (61.5)
33 (21.9) 118 (78.1)
.061
12 (36.4) 21 (63.6)
33 (21.9) 118 (78.1)
.066
31 (32.3) 65 (67.7)
33 (21.9) 118 (78.1)
.048
17 (28.8) 42 (71.2)
33 (21.9) 118 (78.1)
.188
24 (15.5) 131 (84.5)
24 (15.9) 127 (84.1)
.523
3 (11.5) 23 (88.5)
24 (15.9) 127 (84.1)
.410
5 (15.2) 28 (84.8)
24 (15.9) 127 (84.1)
.578
14 (14.6) 82 (85.4)
24 (15.9) 127 (84.1)
.465
9 (15.3) 50 (84.7)
24 (15.9) 127 (84.1)
.547
19 (12.3) 136 (87.7)
14 (9.3) 137 (90.7)
.256
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
14 (14.6) 82 (85.4)
14 (9.3) 137 (90.7)
.141
4 (6.8) 55 (93.2)
14 (9.3) 137 (90.7)
.393
40 (25.8) 115 (74.2)
26 (17.2) 125 (82.8)
.045
6 (23.1) 20 (76.9)
26 (17.2) 125 (82.8)
.318
9 (27.3) 24 (72.7)
26 (17.2) 125 (82.8)
.139
28 (29.2) 68 (70.8)
26 (17.2) 125 (82.8)
.021
11 (18.6) 48 (81.4)
26 (17.2) 125 (82.8)
.475
32 (20.7) 123 (79.3)
14 (9.3) 137 (90.7)
.004
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
10 (30.3) 23 (69.7)
14 (9.3) 137 (90.7)
.003
26 (27.1) 70 (72.9)
14 (9.3) 137 (90.7)
.000
6 (10.2) 53 (89.8)
14 (9.3) 137 (90.7)
.512
29 (18.7) 126 (81.3)
24 (15.9) 127 (84.1)
.309
5 (19.2) 21 (80.8)
24 (15.9) 127 (84.1)
.427
4 (12.1) 29 (87.9)
24 (15.9) 127 (84.1)
.405
19 (19.8) 77 (80.2)
24 (15.9) 127 (84.1)
.268
10 (17.0) 49 (83.0)
24 (15.9) 127 (84.1)
.500
26 (16.8) 129 (83.2)
7 (4.6) 144 (95.4)
.000
5 (19.2) 21 (80.8)
7 (4.6) 144 (95.4)
.018
8 (24.2) 25 (75.8)
7 (4.6) 144 (95.4)
.001
22 (22.9) 74 (77.1)
7 (4.6) 144 (95.4)
.000
4 (6.8) 55 (93.2)
7 (4.6) 144 (95.4)
.373
27 (17.4) 128 (82.6)
18 (11.9) 133 (88.1)
.116
3 (11.5) 23 (88.5)
18 (11.9) 133 (88.1)
.628
9 (27.3) 24 (72.7)
18 (11.9) 133 (88.1)
.029
17 (17.7) 79 (82.3)
18 (11.9) 133 (88.1)
.139
10 (17.0) 49 (83.0)
18 (11.9) 133 (88.1)
.227
20 (12.9) 135 (87.1)
14 (9.3) 137 (90.7)
.204
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
17 (17.7) 79 (82.3)
14 (9.3) 137 (90.7)
.041
3 (5.1) 56 (94.9)
14 (9.3) 137 (90.7)
.242
0 (0.0) 155 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 26 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 33 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 96 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 59 (100.0)
0 (0.0) 151 (100.0)
n/a
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Present
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative
Present
Abdominal pain disorders
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Table IV. Symptoms of orthostatic intolerance upon standing (10 minutes)
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Nausea and vomiting disorders
All FGIDs
Symptoms
Positive
Negative
155 (50.7%)
151 (49.3%)
OR 95% CI
P
Positive
Negative
26 (14.7%)
151 (85.3%)
Abdominal pain disorders
OR 95% CI
P
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Positive
Negative
33 (17.9%)
151 (82.1%)
OR
64 (42.4) 87 (57.6)
1.00 1.69
95% CI
P
Positive
Negative
96 (38.9%)
151 (61.1%)
OR 95% CI
P
Positive
Negative
59 (28.1%)
151 (71.9%)
OR IC95%
P
Orthostatic intolerance
No Yes
49 (31.6) 106 (68.4)
64 (42.4) 1.00 87 (57.6) 1.59
0.972.61
9 (34.6) .0509 17 (65.4)
64 (42.4) 1.00 87 (57.6) 1.38
0.543.77
10 (30.3) .4573 23 (69.7)
0.714.26
30 (31.3) .1998 66 (68.7)
64 (42.4) 1.00 87 (57.6) 1.61
0.912.88
19 (32.3) .0790 40 (67.8)
64 (42.4) 1.00 87 (57.6) 1.54 0.78- .1750 3.10
OH
No Yes
153 (98.7) 148 (98.0) 1.00 2 (1.3) 3 (2.0) 0.64
0.055.72
.6309
26 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
26 (100.0) 150 (99.3) 0 (0.0) 1 (0.7)
n/a
33 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
94 (97.9) 148 (98.0) 1.00 2 (2.1) 3 (2.0) 1.04
0.089.33
.9581
59 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
POTS
No Yes
150 (96.8) 150 (99.3) 1.00 5 (3.2) 1 (0.7) 5
0.54- .1059 237.99
30 (90.9) 3 (9.1)
150 (99.3) 1.00 1 (0.7) 15.0
1.13- .0026 792.33
93 (96.9) 150 (99.3) 1.00 3 (3.1) 1 (0.7) 4.83
0.37- .1350 255.63
57 (96.6) 2 (3.4)
150 (99.3) 1.00 1 (0.7) 5.26 0.26- .1344 312.48
n/a, not applicable. Bold values are statistically significant.
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Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
Table V. Relationship between FGIDs and orthostatic intolerance, OH, and POTS
Diagnosis
All FGIDs
Nausea and vomiting disorders
Beighton score
Beighton score
Positive
Negative
87 (28.4%)
219 (71.6%)
OR 95% CI
P
Beighton score
Positive
Negative
48 (27.1%)
129 (72.9%)
OR 95% CI
P
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Abdominal pain disorders
Beighton Score
Positive
Negative
52 (28.3%)
132 (71.7%)
OR 95% CI
P
Beighton score
Positive
Negative
72 (29.2%)
175 (70.9%)
OR 95% CI
P
Positive
Negative
59 (28.1%)
151 (71.9%)
OR 95% CI
P
Orthostatic intolerance
No Yes
31 (35.6) 82 (37.4) 1.00 56 (64.4) 137 (62.6) 1.08
0.621.88
54 (41.9) 1.00 75 (58.1) 1.09
127 (98.5) 1.00 2 (1.5) 1.35
0.532.30
18 (34.6) .7844 34 (65.4)
56 (42.4) 1.00 76 (57.6) 1.39
51 (98.1) 1 (1.9)
130 (98.5) 1.00 2 (1.5) 1.27
0.682.89
24 (33.3) 70 (40.0) 1.00 .3307 48 (66.7) 105 (60.0) 1.33
0.722.49
23 (39.0) .3267 36 (61.0)
60 (39.7) 1.00 91 (60.3) 1.03
149 (98.7) 1.00 2 (1.3) 1.28
.9202
No Yes
86 (98.9) 215 (98.2) 1.00 1 (1.2) 4 (1.8) 0.62
0.016.44
.6735
47 (97.9) 1 (2.1)
0.014.54
.5188
48 (100.0) 128 (99.2) 0 (0.0) 1 (0.8)
0.0226.46
.8071
0.0224.94
.8440
71 (98.6) 171 (97.7) 1.00 1 (1.4) 4 (2.3) 0.60
0.016.23
.6492
58 (98.3) 1 (1.7)
0.0225.08
.8389
0.0110.25
.8539
59 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
POTS
No Yes n/a, not applicable.
86 (98.9) 214 (97.7) 1.00 1 (1.2) 5 (2.3) 0.49
n/a
52 (100.0) 128 (97.0) 0 (0.0) 4 (3.0)
n/a
71 (98.6) 172 (98.3) 1.00 1 (1.4) 3 (1.7) 0.80
n/a
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0.532.01
OH
19 (39.6) .7672 29 (60.4)
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Table VI. Relation between joint hypermobility and orthostatic intolerance, OH, and POTS
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F
unctional gastrointestinal disorders (FGIDs) represent a major health burden worldwide.1 Patients consulting for FGIDs at tertiary care centers frequently present with joint hypermobility2 and symptoms of autonomic nervous system (ANS) dysfunction3 that manifest as orthostatic intolerance. Common forms of orthostatic intolerance include orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS).4 Orthostatic intolerance is characterized by the development of somatic symptoms with upright posture that improve with recumbence. POTS represents a common form of chronic orthostatic intolerance. In children and adolescents, the diagnosis of POTS is made when a sustained and symptomatic increase in heart rate (HR) occurs in the upright position, without a decrease in blood pressure (BP). Children with orthostatic intolerance whose BP decreases when they are in an upright position are diagnosed as having OH.5 Patients seeking a consultation for FGIDs alone, and patients seeking a consultation for either ANS dysfunction and/or joint hypermobility, report similar comorbidities. These include anxiety, depression, chronic fatigue, headaches, and sleep problems.5 As the pathophysiology of FGIDs remains unclear,6 it is important to understand whether the comorbidities of FGIDs and ANS dysfunction are pathophysiologically linked, are due to chance, or result from the selection bias of complex patients who seek a consultation at tertiary care centers. Clarifying whether these are true associations could open the door to novel treatments for a group of gastrointestinal disorders with poor outcomes. We conducted a study to evaluate the prevalence of orthostatic intolerance and joint hypermobility in schoolchildren with and without FGIDs and to assess ANS dysfunction in children with FGIDs and joint hypermobility. We hypothesized that patients with FGIDs would be more likely to present with orthostatic intolerance and those with orthostatic intolerance would be more likely to have POTS, OH, and joint hypermobility.
ANS BP FGID HR OH POTS
Autonomic nervous system Blood pressure Functional gastrointestinal disorder Heart rate Orthostatic hypotension Postural orthostatic tachycardia syndrome
From the 1Department of Pediatrics, Universidad del Valle, Colombia; 2Program in Clinical Medicine and Public Health, University of Granada, Spain; 3University of Miami Miller School of Medicine, Miami, FL The authors declare no conflicts of interest. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.11.009
1
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Methods Parents of schoolchildren between the ages of 10 and 18 years attending public schools from 3 Colombian cities (Cali [southwest region], Palmira [southwest region], and Bucaramanga [northeastern region]) were invited to participate in the study through informative letters that did not reveal the aims and hypothesis of the study. Children with a history of organic gastrointestinal or metabolic diseases, eating disorders, or those who had signs of dehydration after physical examination by physicians were excluded. Participants completed age-appropriate validated questionnaires to diagnose FGIDs according to the Rome IV criteria (Questionnaire on Pediatric Gastrointestinal Symptoms-IV).7 Children who met criteria for at least 1 FGID were matched with a healthy control from the same sex and age. Cases and controls completed questionnaires regarding symptoms commonly associated with orthostatic intolerance. Surveys included historical binary questions (yes/no) on the incidence of dizziness, nausea, headaches, tremors, blurred vision, vertigo, anxiety, near syncope and syncope, sweating, and palpitations triggered by standing in the 2 months before the investigation. All sign/symptoms were again assessed during the recumbent (10 minutes) and standing phase (2, 5, and 10 minutes) of the investigation. Baseline HR and BP measures were obtained at each interval using an automatic blood pressure monitor (Honsun SCIAN LD-582; Shanghai Honsun International Trade Co Ltd, Shanghai, China). Patient’s excess of joint mobility was evaluated with the Beighton score (bilateral hypermobility of the fifth fingers, thumbs, knees, and elbows, and the ability to place palms flat on the floor with knees straight). A mechanical goniometer (Goniometro Professional; MSD, Kenilworth, New Jersey) was used to assist with joint mobility measures. Testing was conducted in each school at a quiet, temperature-controlled, isolated room absent of distractions. Members of the research team were present throughout the study to help complete questionnaires and to observe and record any symptoms that developed during testing. Orthostatic intolerance was characterized by having ³1 symptoms upon standing, such as lightheadedness, palpitations, generalized weakness, blurred vision, exercise intolerance, and fatigue. OH was defined as a drop in BP within 2 minutes of standing up of at least 20 mm Hg systolic blood pressure or at least 10 mm Hg diastolic BP.8 POTS was defined as an increase of HR of at least 40 beats per minute during the time period of upright position (10 minutes) without a decrease of systolic BP ³20 mm Hg,5 in adolescents £18 years. Joint hypermobility was clinically defined by the presence of a Beighton score of at least 4 of 9.9 Statistical Analyses Age, sex, and the diagnosis of orthostatic intolerance, OH, and POTS were assessed and compared between the groups of children with and without FGIDs. FGIDs were categorized 2
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by disorders of nausea and vomiting, including cyclic vomiting syndrome, functional nausea and vomiting disorders, rumination syndrome, and aerophagia, and by functional abdominal pain disorders, including functional dyspepsia, irritable bowel syndrome, abdominal migraines, and functional abdominal pain—not otherwise specified, as well as functional defecation disorders, including functional constipation and functional nonretentive incontinence. Data were calculated as percentages, means (SD; 95% CI). The differences in characteristics between schoolchildren with and without FGIDs were compared with a t-test for continuous variables and with a Fisher exact test (2 2 contingency tables) for categorical variables. Univariate analysis and bivariate analysis were calculated. ORs were calculated. Statistical significance was set at P < .05. The study was approved by the institutional review board and Human Subjects Committee of Universidad del Valle of Cali, Colombia. All participating children and their parents provided written consent.
Results A total of 1630 schoolchildren completed the Questionnaire on Pediatric Gastrointestinal Symptoms-IV. Of these, 267 children met criteria for FGIDs (16.2%) according to Rome IV criteria and were invited to participate in the study. One-hundred fifty-five of 267 children agreed to proceed with the second step of the study and underwent testing (10-12 years old, n = 41; 13-18 years old, n = 114). The group of children with FGIDs were matched with 155 healthy controls of similar age and sex without FGIDs from the same schools. Both groups were balanced in terms of age and sex (Figure). Four children did not follow up for further testing and were excluded from the study. No subjects were excluded due to dehydration. A total of 306 children with an age range of 10-18 years (109 females, P = .129) were finally included in the study (Figure). The most prevalent FGID Rome IV diagnostic category was functional defecation disorders (61.94%), followed by functional abdominal pain disorders (21.29%) and functional nausea and vomiting disorders (16.77%) Five children in the group of functional nausea and vomiting had overlap with other FGIDs (Table I).
Relationship between FGIDs and Symptoms of Orthostatic Intolerance by History (2 Months) Of 12 characteristic features of orthostatic intolerance that were surveyed, children with FGIDs reported a significantly greater frequency of 10 of them. There was no significant difference in reported prevalence of dizziness and loss of consciousness (reported by only 6 children) between those with FGIDs and those without. When defecation disorders were removed from analysis, 5 symptoms lost significance (headache, tremulousness, feeling hot, vertigo, and sweatiness) (Table II). Velasco-Benitez et al
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ORIGINAL ARTICLES
S creen in g
I d e n ti fic a tio n
Table I. Diagnosis of FGIDs (Rome IV criteria) Disorders (N = 155)
School-children invited to participate (n=2153)
Completed the QPGS IV questionnaires (n=1630)
No FGIDs (n=1363)
E l i g i b il i t y
FGIDs (n=267)
Disorders of functional nausea and functional vomiting Cyclic vomiting syndrome Functional nausea and vomiting disorders Nausea Vomiting Rumination syndrome Aerophagia Functional abdominal pain disorders Functional dyspepsia Irritable bowel syndrome Abdominal migraines Functional abdominal pain Functional defecation disorders Functional constipation Functional nonretentive encopresis
33* (21.29) 9 (5.81) 7 (4.52) 1 (0.65) 6 (3.87) 5 (3.23) 5 (3.23) 33 (21.29) 21 (13.55) 3 (1.94) 7 (4.52) 2 (1.29) 96 (61.94) 94 (60.65) 2 (1.29)
*There was an overlap of 5 children with more than 1 disorder.
Agreed to participate (n=155) In c lu d e d
N (%)
Matched controls agreed to participate (n=155)
Controls withdrew (n=4)
Figure. Flow diagram of patient enrollment. QPGS IV, Questionnaire on Pediatric Gastrointestinal Symptoms-IV.
Relationship between FGIDs and Symptoms of Orthostatic Intolerance at Recumbency (10 Minutes) There was no significant difference in prevalence in any of the symptoms between those with FGIDs and those without FGIDs during recumbency, even when defecation disorders were removed from analysis (Table III). Relationship between FGIDs and Symptoms of Orthostatic Intolerance at Orthostasis (10 Minutes) Of 12 characteristic features of orthostatic intolerance that were surveyed, children with FGIDs reported a significant greater frequency of 6 of them during orthostasis. When defecation disorders were removed from analysis, all findings lost significance (Table IV; available at www.jpeds.com). Relationship between FGIDs and Orthostatic Intolerance, OH, and POTS One hundred six of 155 (68.4%) children with FGIDs had orthostatic intolerance (P = .0509), trending toward statistical significance. Overall, there was no significant difference in prevalence of OH and POTS between those with FGIDs and those without. Two of 155 (1.3%) children with FGIDs had OH (P = .6309), and 5 of 155 (3.2%) children with FGIDs had POTS (P = .1059). When defecation disorders were
removed from analysis, there was no significant difference in prevalence of orthostatic intolerance and POTS between those with FGIDs and those without (Table V; available at www.jpeds.com). Relationship between Joint Hypermobility and Orthostatic Intolerance, OH, and POTS Eighty-seven of 306 (28.4%) children met criteria for joint hypermobility. Of the 87 with joint hypermobility, 56 had orthostatic intolerance (64.4%) (P = .7672). Only 1 child had both joint hypermobility and OH (1.2%) (P = .6735). Similarly, only 1 child had both joint hypermobility and POTS (1.2%) (P = .5188). Overall, there was no significant difference in prevalence of orthostatic intolerance, OH, and POTS between those with joint hypermobility and those without, even when defecation disorders were removed from analysis (Table VI; available at www.jpeds.com).
Discussion There have been several studies investigating the association between FGIDs, orthostatic intolerance, and joint hypermobility. Those studies have shown a high prevalence of autonomic disorders and joint hypermobility in individuals with FGIDs.2,10-12 However, all those studies have been tertiary clinic based. We were unable to establish whether there was a true association between autonomic disorders and FGIDs in children or whether it was the product of selection bias among those who seek a consult in specialized clinics. This study evaluated the prevalence of POTS and OH at the community level in children with or without FGIDs. We hypothesized that patients with FGIDs and joint hypermobility would be more likely to present with orthostatic intolerance. We found that many children in the community have symptoms of orthostatic intolerance, and that children with FGIDs more frequently reported a history of orthostatic intolerance than those without FGIDs. Although the difference in findings does not portray a statistically significant difference, it shows a clear trend (P = .0509). When recumbent,
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
3
Nausea and vomiting disorders
All FGIDs
Symptoms
Absent
Absent
Present
Absent
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
P
n = 33 (%)
n = 151 (%)
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
103 (66.4) 52 (33.6)
87 (57.6) 64 (42.4)
.070
16 (61.5) 10 (38.5)
87 (57.6) 64 (42.4)
.440
25 (75.8) 8 (24.2)
87 (57.6) 64 (42.4)
.039
62 (64.6) 34 (35.4)
87 (57.6) 64 (42.4)
.169
41 (69.5) 18 (30.5)
87 (57.6) 64 (42.4)
.076
52 (33.6) 103 (66.4)
27 (17.9) 124 (82.2)
.001
6 (23.1) 20 (76.9)
27 (17.9) 124 (82.1)
.348
12 (36.4) 21 (63.6)
27 (17.9) 124 (82.1)
.020
32 (33.3) 64 (66.7)
27 (17.9) 124 (82.2)
.005
20 (33.9) 39 (66.1)
27 (17.9) 124 (82.2)
.012
88 (56.8) 67 (42.2)
69 (45.7) 82 (54.3)
.034
9 (34.6) 17 (65.4)
69 (45.7) 82 (54.3)
.202
20 (60.6) 13 (39.4)
69 (45.7) 82 (54.3)
.087
57 (59.4) 39 (40.6)
69 (45.7) 82 (54.3)
.024
31 (52.5) 28 (47.5)
69 (45.7) 82 (54.3)
.230
32 (20.7) 123 (79.3)
18 (11.9) 133 (88.1)
.028
2 (7.7) 24 (92.3)
18 (11.9) 133 (88.1)
.408
9 (27.3) 24 (72.7)
18 (11.9) 133 (88.1)
.029
24 (25.0) 72 (75.0)
18 (11.9) 133 (88.1)
.007
8 (13.6) 51 (86.4)
18 (11.9) 133 (88.1)
.454
77 (49.7) 78 (50.3)
41 (27.2) 110 (72.8)
.000
8 (30.8) 18 (69.2)
41 (27.2) 110 (72.8)
.433
20 (60.6) 13 (39.4)
41 (27.2) 110 (72.8)
.000
49 (51.0) 47 (49.0)
41 (27.2) 110 (72.8)
.000
28 (47.5) 31 (52.5)
41 (27.2) 110 (72.8)
.004
56 (36.1) 99 (63.9)
40 (26.5) 111 (73.5)
.045
8 (30.8) 18 (69.2)
40 (26.5) 111 (73.5)
.406
16 (48.5) 17 (51.5)
40 (26.5) 111 (73.5)
.013
38 (39.6) 58 (60.4)
40 (26.5) 111 (73.5)
.022
18 (30.5) 41 (69.5)
40 (26.5) 111 (73.5)
.336
45 (29.0) 110 (71.0)
34 (22.5) 117 (877.5)
.000
6 (23.1) 20 (76.9)
34 (22.5) 117 (77.5)
.563
9 (27.3) 24 (72.7)
34 (22.5) 117 (77.5)
.352
32 (33.3) 64 (66.7)
34 (22.5) 117 (877.5)
.043
13 (22.0) 46 (78.0)
34 (22.5) 117 (877.5)
.549
48 (31.0) 107 (69.0)
28 (18.5) 123 (81.5)
.008
10 (38.5) 16 (61.5)
28 (18.5) 123 (81.5)
.026
13 (39.4) 20 (60.6)
28 (18.5) 123 (81.5)
.011
30 (31.3) 66 (68.7)
28 (18.5) 123 (81.5)
.017
18 (30.5) 41 (69.5)
28 (18.5) 123 (81.5)
.047
44 (28.4) 111 (71.6)
15 (9.9) 136 (90.1)
.000
5 (19.2) 21 (80.8)
15 (9.9) 136 (90.1)
.147
14 (42.4) 19 (57.6)
15 (9.9) 136 (90.1)
.000
30 (31.3) 66 (68.7)
15 (9.9) 136 (90.1)
.000
14 (23.7) 45 (76.3)
15 (9.9) 136 (90.1)
.011
51 (32.9) 104 (67.1)
35 (23.2) 116 (76.8)
.039
9 (34.6) 17 (65.4)
35 (23.2) 116 (76.8)
.158
15 (45.5) 18 (54.5)
35 (23.2) 116 (76.8)
.010
39 (40.6) 57 (59.4)
35 (23.2) 116 (76.8)
.003
12 (20.3) 47 (79.7)
35 (23.2) 116 (76.8)
.403
37 (23.9) 118 (76.1)
17 (11.3) 134 (88.7)
.003
6 (23.1) 20 (76.9)
17 (11.3) 134 (88.7)
.095
12 (36.4) 21 (63.6)
17 (11.3) 134 (88.7)
.001
24 (25.0) 72 (75.0)
17 (11.3) 134 (88.7)
.004
13 (22.0) 46 (78.0)
17 (11.3) 134 (88.7)
.040
3 (1.9) 152 (98.1)
3 (2.0) 148 (98.0)
.645
0 (0.0) 26 (100.0)
3 (2.0) 148 (98.0)
.619
1 (3.0) 32 (97.0)
3 (2.0) 148 (98.0)
.550
2 (2.1) 94 (97.9)
3 (2.0) 148 (98.0)
.645
1 (1.7) 58 (98.3)
3 (2.0) 148 (98.0)
.686
Volume -
Bold values are statistically significant.
www.jpeds.com
Present
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Velasco-Benitez et al
Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative
Present
Abdominal pain disorders
THE JOURNAL OF PEDIATRICS
4
Table II. Symptoms of orthostatic intolerance by history (2 months)
- 2019
Nausea and vomiting disorders
All FGIDs
Symptoms Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative n/a, not available.
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
58 (37.4) 97 (62.6)
54 (35.8) 97 (64.2)
.428
9 (34.6) 17 (65.4)
15 (9.7) 140 (90.3)
13 (8.6) 138 (91.4)
.450
42 (27.3) 112 (72.7)
44 (29.1) 107 (70.9)
27 (17.4) 128 (82.6)
Abdominal pain disorders Present
Absent
P
n = 33 (%)
n = 151 (%)
54 (35.8) 97 (64.2)
.549
13 (39.4) 20 (60.6)
1 (3.9) 25 (96.1)
13 (8.6) 138 (91.4)
.358
.407
7 (26.9) 19 (73.1)
44 (29.1) 107 (70.9)
24 (15.9) 127 (84.1)
.419
2 (7.7) 24 (92.3)
22 (14.2) 133 (85.8)
26 (17.2) 125 (82.8)
.284
22 (14.2) 133 (85.8)
27 (17.9) 124 (82.1)
37 (23.9) 118 (76.1)
Nausea, vomiting, and abdominal pain disorders
Defecation disorders Present
Absent
Present
Absent
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
54 (35.8) 97 (64.2)
.419
44 (45.8) 52 (54.2)
54 (35.8) 97 (64.2)
.075
14 (23.7) 45 (76.3)
54 (35.8) 97 (64.2)
.064
2 (6.1) 31 (93.9)
13 (8.6) 138 (91.4)
.473
11 (11.5) 85 (88.5)
13 (8.6) 138 (91.4)
.300
4 (6.8) 55 (93.2)
13 (8.6) 138 (91.4)
.452
.511
12 (36.4) 21 (63.6)
44 (29.1) 107 (70.9)
.268
30 (31.6) 65 (68.4)
44 (29.1) 107 (70.9)
.395
12 (20.3) 47 (79.7)
44 (29.1) 107 (70.9)
.130
24 (15.9) 127 (84.1)
.221
8 (24.2) 25 (75.8)
24 (15.9) 127 (84.1)
.184
21 (21.9) 75 (78.1)
24 (15.9) 127 (84.1)
.154
6 (10.2) 53 (89.8)
24 (15.9) 127 (84.1)
.201
3 (11.5) 23 (88.5)
26 (17.2) 125 (82.8)
.346
7 (21.2) 26 (78.8)
26 (17.2) 125 (82.8)
.374
15 (15.6) 81 (84.4)
26 (17.2) 125 (82.8)
.443
7 (11.9) 52 (88.1)
26 (17.2) 125 (82.8)
.231
.235
4 (15.4) 22 (84.6)
27 (17.9) 124 (82.1)
.506
4 (12.1) 29 (87.9)
27 (17.9) 124 (82.1)
.303
12 (12.5) 84 (87.5)
27 (17.9) 124 (82.1)
.171
10 (17.0) 49 (83.0)
27 (17.9) 124 (82.1)
.525
27 (17.9) 124 (82.1)
.125
7 (26.9) 19 (73.1)
27 (17.9) 124 (82.1)
.205
10 (30.3) 23 (69.7)
27 (17.9) 124 (82.1)
.088
22 (22.9) 74 (77.1)
27 (17.9) 124 (82.1)
.210
15 (25.4) 44 (74.6)
27 (17.9) 124 (82.1)
.150
32 (20.7) 123 (79.3)
25 (16.6) 126 (83.4)
.220
6 (23.1) 20 (76.9)
25 (16.6) 126 (83.4)
.288
6 (18.2) 27 (81.8)
25 (16.6) 126 (83.4)
.497
21 (21.9) 75 (78.1)
25 (16.6) 126 (83.4)
.189
11 (18.6) 48 (81.4)
25 (16.6) 126 (83.4)
.430
19 (12.3) 136 (87.7)
14 (9.3) 137 (90.7)
.256
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
15 (15.6) 81 (84.4)
14 (9.3) 137 (90.7)
.096
4 (6.8) 55 (93.2)
14 (9.3) 137 (90.7)
.393
20 (12.9) 135 (87.1)
16 (10.6) 135 (89.4)
.327
3 (11.5) 23 (88.5)
16 (10.6) 135 (89.4)
.553
8 (24.2) 25 (75.8)
16 (10.6) 135 (89.4)
.040
11 (11.5) 85 (88.5)
16 (10.6) 135 (89.4)
.494
9 (15.3) 50 (84.7)
16 (10.6) 135 (89.4)
.238
22 (14.2) 133 (85.8)
16 (10.6) 135 (89.4)
.218
3 (11.5) 23 (88.5)
16 (10.6) 135 (89.4)
.553
5 (15.2) 28 (84.8)
16 (10.6) 135 (89.4)
.315
19 (19.8) 77 (80.2)
16 (10.6) 135 (89.4)
.035
3 (5.1) 56 (94.9)
16 (10.6) 135 (89.4)
.163
0 (0.0) 155 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 26 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 33 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 96 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 59 (100.0)
0 (0.0) 151 (100.0)
n/a
5
ORIGINAL ARTICLES
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
Table III. Symptoms of orthostatic intolerance at recumbency (10 minutes)
THE JOURNAL OF PEDIATRICS
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there was no significant difference in the prevalence of somatic symptoms in those with and without FGIDs. However, upon orthostasis, children with FGIDs were significantly more likely to feel dizziness, vertigo, nausea, headaches, tremors, blurred vision, hot, sweatiness, and near faint than patients without FGIDs. The fact that the history of orthostatic intolerance was more likely to match the incidence of symptoms with orthostasis but not with recumbence suggests the presence of an ANS dysfunction in those with FGIDs. However, our study showed that very few children with FGIDs had OH (1.3%) and POTS (3.2%). This suggests that selection bias may explain the presence of a significant greater prevalence of OH and POTS in children with FGIDs seen in tertiary centers.11 Nevertheless, due to the low frequency of these disorders in our sample, we cannot exclude that our study was not powered to find a significant difference in OH and POTS between children with and without FGIDs. In fact, POTS was more common in children with FGIDs without reaching statistical significance. Another important finding of the current study is that the history of orthostatic intolerance and basic clinic-based testing may be a reliable tool to discriminate children who may need formal autonomic testing for POTS and OH. A thorough history and initial testing for symptoms of orthostatic intolerance, HR, and BP in clinic in recumbent and orthostatic position may be warranted before referring patients to autonomic medicine. Autonomic specialists are scarce and testing is costly and not readily available in all centers. Moreover, due to the high prevalence of symptoms of orthostatic intolerance in children with FGIDs, conducting tilt-table testing in all children with FGIDs who report symptoms of autonomic disorders would be an untenable burden for the healthcare system. Taken together, physicians should aim to treat orthostatic intolerance when clinically relevant and refer those who do not improve to an autonomic medicine specialist for formal diagnosis and management. Practitioners should then be aware of the various treatment modalities applied to the treatment of autonomic disorders, as some of them can be recommended as primary measures to improve the patient’s symptoms. These include increased salt intake and fluids, progressive exercise, compression stockings up to the waist, beta-adrenoreceptor blockers, and corticosteroids.13 Our study raises an important issue by suggesting that presence of laxity of connective tissue by themselves are not sufficient to cause FGIDs or autonomic dysfunction. Children with joint hypermobility were not more likely to experience FGIDs, orthostatic intolerance, OH, and POTS. Similar to our findings in the relationship between FGIDs and orthostatic intolerance, a large number of children with joint hypermobility had orthostatic intolerance (64.4%). However, only 1 child with joint hypermobility met the criteria for OH (1.2%), and 1 for POTS (1.2%). Among the strengths of our study were the presence of local physicians onsite for history and testing. The school setting allowed us to obtain data from community children without the 6
Volume -
selection bias inherent to consultation patterns. Some of the additional strengths of our study include the large sample size, the use of validated questionnaires to diagnose FGIDs, and a goniometer to measure joint hypermobility. Orthostatic intolerance and BP and HR were measured under control environment that included temperature and noise. Our study also has limitations. The lack of information on medical consultation does not allow us to compare our data with clinic data. Approximately 60% patients who screened positive for FGIDs agreed to be enrolled in the study for further testing of POTS and hypermobility. The 40% who did not agree to be tested could have skewed the results of the prevalence of both group of conditions. Although we found a relationship between FGIDs and some symptoms of orthostatic intolerance, the design of our study does not allow to explain this relation. Also, we cannot establish whether the severity of symptoms worsened with orthostasis, as our study did not have a symptom intensity scale. The lack of this scale is unfortunate. In retrospect, we should have included not only a binary questionnaire but also a severity questionnaire. In addition, we did not use a tilt test for diagnosing orthostatic intolerance, and although OH requires measures of BP at 3 minutes of standing, children were evaluated at 2 minutes and 10 minutes of standing instead. In conclusion, children with FGIDs were only found to have a greater prevalence of symptoms of orthostatic intolerance but were not more likely to have OH and POTS as compared with the children without FGIDs. Thus, it is unlikely that the high frequency of reports of orthostatic intolerance in children with FGIDs could just be the result of selection bias. Based on the high prevalence of orthostatic intolerance and infrequent diagnosis of POTS and OH, it could be reasoned that the diagnostic criteria for POTS and OH may be too strict and therefore unintentionally dismiss individuals who still have symptoms. Children with joint hypermobility also were not found to have a greater prevalence of orthostatic intolerance, OH, and POTS, as compared with the children without joint hypermobility. This study reinforces the paradigm of the multifactorial nature of underlying pathophysiology of FGIDs. Large multinational studies are needed confirm our findings. n Submitted for publication Aug 12, 2019; last revision received Oct 7, 2019; accepted Nov 7, 2019. Reprint requests: Miguel Saps, MD, 1601 NW 12th Ave, Suite 3005A, Miami, FL 33136. E-mail: [email protected]; [email protected]
References 1. Wu JC. Psychological co-morbidity in functional gastrointestinal disorders: epidemiology, mechanisms and management. J Neurogastroenterol Motil 2012;18:13-8. 2. Kovacic K, Chelimsky TC, Sood MR, Simpson P, Nugent M, Chelimsky G. Joint hypermobility: a common association with complex functional gastrointestinal disorders. J Pediatr 2014;165:973-8. 3. Chelimsky G, Boyle JT, Tusing L, Chelimsky TC. Autonomic abnormalities in children with functional abdominal pain: coincidence or etiology? J Pediatr Gastroenterol Nutr 2001;33:47-53.
Velasco-Benitez et al
- 2019 4. Sullivan SD, Hanauer J, Rowe PC, Barron DF, Darbari A, OlivaHemker M. Gastrointestinal symptoms associated with orthostatic intolerance. J Pediatr Gastroenterol Nutr 2005;40:425-8. 5. Stewart JM, Boris JR, Chelimsky G, Fischer PR, Fortunato JE, Grubb BP, et al. Pediatric disorders of orthostatic intolerance. Pediatrics 2018;141:e20171673. 6. Ferreira-Maia AP, Matijasevich A, Wang YP. Epidemiology of functional gastrointestinal disorders in infants and toddlers: a systematic review. World J Gastroenterol 2016;22:6547-58. 7. Zeevenhooven J, Koppen IJ, Benninga MA. The New Rome IV Criteria for functional gastrointestinal disorders in infants and toddlers. Pediatr Gastroenterol Hepatol Nutr 2017;20:1-13. 8. Shen W-K, Sheldon RS, Benditt DG, Cohen MI, Forman DE, Goldberger ZD, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients with Syncope: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017;136:e25-59.
ORIGINAL ARTICLES 9. Saps M, Blom PJJ, Velasco-Benitez CA, Benninga MA. Functional gastrointestinal disorders and joint hypermobility: a school-based study. J Pediatr Gastroenterol Nutr 2018;66:387-90. 10. Chelimsky G, Kovacic K, Nugent M, Mueller A, Simpson P, Chelimsky TC. Comorbid conditions do not differ in children and young adults with functional disorders with or without postural tachycardia syndrome. J Pediatr 2015;167:120-4. 11. Beckers AB, Keszthelyi D, Fikree A, Vork L, Masclee A, Farmer AD, et al. Gastrointestinal disorders in joint hypermobility syndrome/EhlersDanlos syndrome hypermobility type: a review for the gastroenterologist. Neurogastroenterol Motil 2017;29:e13013. 12. Fikree A, Aktar R, Morris JK, Grahame R, Knowles CH, Aziz Q. The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study. Neurogastroenterol Motil 2017;29. 13. Xu WR, Jin HF, Du JB. Pathogenesis and individualized treatment for postural tachycardia syndrome in children. Chin Med J 2016;129: 2241-5.
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
7
Nausea and vomiting disorders
All FGIDs
Symptoms
Absent
Absent
Present
Absent
Present
Absent
Present
Absent
n = 155 (%)
n = 151 (%)
P
n = 26 (%)
n = 151 (%)
P
n = 33 (%)
n = 151 (%)
P
n = 96 (%)
n = 151 (%)
P
n = 59 (%)
n = 151 (%)
P
48 (31.0) 107 (69.0)
24 (15.9) 127 (84.1)
.001
5 (19.2) 21 (80.8)
24 (15.9) 127 (84.1)
.427
12 (36.4) 21 (63.6)
24 (15.9) 127 (84.1)
.010
36 (37.5) 60 (62.5)
24 (15.9) 127 (84.1)
.000
12 (20.3) 47 (79.7)
24 (15.9) 127 (84.1)
.282
20 (12.9) 135 (87.1)
10 (6.6) 141 (93.4)
.048
3 (11.5) 23 (88.5)
10 (6.6) 141 (93.4)
.293
5 (15.2) 28 (84.8)
10 (6.6) 141 (93.4)
.106
15 (15.6) 81 (84.4)
10 (6.6) 141 (93.4)
.020
5 (8.5) 54 (91.5)
10 (6.6) 141 (93.4)
.418
48 (31.0) 107 (69.0)
33 (21.9) 118 (78.1)
.047
10 (38.5) 16 (61.5)
33 (21.9) 118 (78.1)
.061
12 (36.4) 21 (63.6)
33 (21.9) 118 (78.1)
.066
31 (32.3) 65 (67.7)
33 (21.9) 118 (78.1)
.048
17 (28.8) 42 (71.2)
33 (21.9) 118 (78.1)
.188
24 (15.5) 131 (84.5)
24 (15.9) 127 (84.1)
.523
3 (11.5) 23 (88.5)
24 (15.9) 127 (84.1)
.410
5 (15.2) 28 (84.8)
24 (15.9) 127 (84.1)
.578
14 (14.6) 82 (85.4)
24 (15.9) 127 (84.1)
.465
9 (15.3) 50 (84.7)
24 (15.9) 127 (84.1)
.547
19 (12.3) 136 (87.7)
14 (9.3) 137 (90.7)
.256
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
14 (14.6) 82 (85.4)
14 (9.3) 137 (90.7)
.141
4 (6.8) 55 (93.2)
14 (9.3) 137 (90.7)
.393
40 (25.8) 115 (74.2)
26 (17.2) 125 (82.8)
.045
6 (23.1) 20 (76.9)
26 (17.2) 125 (82.8)
.318
9 (27.3) 24 (72.7)
26 (17.2) 125 (82.8)
.139
28 (29.2) 68 (70.8)
26 (17.2) 125 (82.8)
.021
11 (18.6) 48 (81.4)
26 (17.2) 125 (82.8)
.475
32 (20.7) 123 (79.3)
14 (9.3) 137 (90.7)
.004
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
10 (30.3) 23 (69.7)
14 (9.3) 137 (90.7)
.003
26 (27.1) 70 (72.9)
14 (9.3) 137 (90.7)
.000
6 (10.2) 53 (89.8)
14 (9.3) 137 (90.7)
.512
29 (18.7) 126 (81.3)
24 (15.9) 127 (84.1)
.309
5 (19.2) 21 (80.8)
24 (15.9) 127 (84.1)
.427
4 (12.1) 29 (87.9)
24 (15.9) 127 (84.1)
.405
19 (19.8) 77 (80.2)
24 (15.9) 127 (84.1)
.268
10 (17.0) 49 (83.0)
24 (15.9) 127 (84.1)
.500
26 (16.8) 129 (83.2)
7 (4.6) 144 (95.4)
.000
5 (19.2) 21 (80.8)
7 (4.6) 144 (95.4)
.018
8 (24.2) 25 (75.8)
7 (4.6) 144 (95.4)
.001
22 (22.9) 74 (77.1)
7 (4.6) 144 (95.4)
.000
4 (6.8) 55 (93.2)
7 (4.6) 144 (95.4)
.373
27 (17.4) 128 (82.6)
18 (11.9) 133 (88.1)
.116
3 (11.5) 23 (88.5)
18 (11.9) 133 (88.1)
.628
9 (27.3) 24 (72.7)
18 (11.9) 133 (88.1)
.029
17 (17.7) 79 (82.3)
18 (11.9) 133 (88.1)
.139
10 (17.0) 49 (83.0)
18 (11.9) 133 (88.1)
.227
20 (12.9) 135 (87.1)
14 (9.3) 137 (90.7)
.204
4 (15.4) 22 (84.6)
14 (9.3) 137 (90.7)
.260
5 (15.2) 28 (84.8)
14 (9.3) 137 (90.7)
.236
17 (17.7) 79 (82.3)
14 (9.3) 137 (90.7)
.041
3 (5.1) 56 (94.9)
14 (9.3) 137 (90.7)
.242
0 (0.0) 155 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 26 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 33 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 96 (100.0)
0 (0.0) 151 (100.0)
n/a
0 (0.0) 59 (100.0)
0 (0.0) 151 (100.0)
n/a
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Present
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Dizziness Positive Negative Nausea Positive Negative Headache Positive Negative Tremulousness Positive Negative Blurry vision Positive Negative Feeling hot Positive Negative Vertigo Positive Negative Feeling anxious Positive Negative Feeling faint Positive Negative Sweatiness Positive Negative Palpitations Positive Negative Loss of consciousness Positive Negative
Present
Abdominal pain disorders
THE JOURNAL OF PEDIATRICS
7.e1
Table IV. Symptoms of orthostatic intolerance upon standing (10 minutes)
Volume -
Velasco-Benitez et al
n/a, not applicable. Bold values are statistically significant.
- 2019
Nausea and vomiting disorders
All FGIDs
Symptoms
Positive
Negative
155 (50.7%)
151 (49.3%)
OR 95% CI
P
Positive
Negative
26 (14.7%)
151 (85.3%)
Abdominal pain disorders
OR 95% CI
P
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Positive
Negative
33 (17.9%)
151 (82.1%)
OR
64 (42.4) 87 (57.6)
1.00 1.69
95% CI
P
Positive
Negative
96 (38.9%)
151 (61.1%)
OR 95% CI
P
Positive
Negative
59 (28.1%)
151 (71.9%)
OR IC95%
P
Orthostatic intolerance
No Yes
49 (31.6) 106 (68.4)
64 (42.4) 1.00 87 (57.6) 1.59
0.972.61
9 (34.6) .0509 17 (65.4)
64 (42.4) 1.00 87 (57.6) 1.38
0.543.77
10 (30.3) .4573 23 (69.7)
0.714.26
30 (31.3) .1998 66 (68.7)
64 (42.4) 1.00 87 (57.6) 1.61
0.912.88
19 (32.3) .0790 40 (67.8)
64 (42.4) 1.00 87 (57.6) 1.54 0.78- .1750 3.10
OH
No Yes
153 (98.7) 148 (98.0) 1.00 2 (1.3) 3 (2.0) 0.64
0.055.72
.6309
26 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
26 (100.0) 150 (99.3) 0 (0.0) 1 (0.7)
n/a
33 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
94 (97.9) 148 (98.0) 1.00 2 (2.1) 3 (2.0) 1.04
0.089.33
.9581
59 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
n/a
POTS
No Yes
150 (96.8) 150 (99.3) 1.00 5 (3.2) 1 (0.7) 5
0.54- .1059 237.99
30 (90.9) 3 (9.1)
150 (99.3) 1.00 1 (0.7) 15.0
1.13- .0026 792.33
93 (96.9) 150 (99.3) 1.00 3 (3.1) 1 (0.7) 4.83
0.37- .1350 255.63
57 (96.6) 2 (3.4)
150 (99.3) 1.00 1 (0.7) 5.26 0.26- .1344 312.48
n/a, not applicable. Bold values are statistically significant.
7.e2
ORIGINAL ARTICLES
Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?
Table V. Relationship between FGIDs and orthostatic intolerance, OH, and POTS
Diagnosis
All FGIDs
Nausea and vomiting disorders
Beighton score
Beighton score
Positive
Negative
87 (28.4%)
219 (71.6%)
OR 95% CI
P
Beighton score
Positive
Negative
48 (27.1%)
129 (72.9%)
OR 95% CI
P
Nausea, vomiting, and abdominal pain disorders
Defecation disorders
Abdominal pain disorders
Beighton Score
Positive
Negative
52 (28.3%)
132 (71.7%)
OR 95% CI
P
Beighton score
Positive
Negative
72 (29.2%)
175 (70.9%)
OR 95% CI
P
Positive
Negative
59 (28.1%)
151 (71.9%)
OR 95% CI
P
Orthostatic intolerance
No Yes
31 (35.6) 82 (37.4) 1.00 56 (64.4) 137 (62.6) 1.08
0.621.88
54 (41.9) 1.00 75 (58.1) 1.09
127 (98.5) 1.00 2 (1.5) 1.35
0.532.30
18 (34.6) .7844 34 (65.4)
56 (42.4) 1.00 76 (57.6) 1.39
51 (98.1) 1 (1.9)
130 (98.5) 1.00 2 (1.5) 1.27
0.682.89
24 (33.3) 70 (40.0) 1.00 .3307 48 (66.7) 105 (60.0) 1.33
0.722.49
23 (39.0) .3267 36 (61.0)
60 (39.7) 1.00 91 (60.3) 1.03
149 (98.7) 1.00 2 (1.3) 1.28
.9202
No Yes
86 (98.9) 215 (98.2) 1.00 1 (1.2) 4 (1.8) 0.62
0.016.44
.6735
47 (97.9) 1 (2.1)
0.014.54
.5188
48 (100.0) 128 (99.2) 0 (0.0) 1 (0.8)
0.0226.46
.8071
0.0224.94
.8440
71 (98.6) 171 (97.7) 1.00 1 (1.4) 4 (2.3) 0.60
0.016.23
.6492
58 (98.3) 1 (1.7)
0.0225.08
.8389
0.0110.25
.8539
59 (100.0) 148 (98.0) 0 (0.0) 3 (2.0)
POTS
No Yes n/a, not applicable.
86 (98.9) 214 (97.7) 1.00 1 (1.2) 5 (2.3) 0.49
n/a
52 (100.0) 128 (97.0) 0 (0.0) 4 (3.0)
n/a
71 (98.6) 172 (98.3) 1.00 1 (1.4) 3 (1.7) 0.80
n/a
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0.532.01
OH
19 (39.6) .7672 29 (60.4)
THE JOURNAL OF PEDIATRICS
7.e3
Table VI. Relation between joint hypermobility and orthostatic intolerance, OH, and POTS
Volume -
Velasco-Benitez et al