All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.
Clinical Gastroenterology and Hepatology 2015;-:-–-
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Acute Anxiety and Anxiety Disorders Are Associated With Impaired Gastric Accommodation in Patients With Functional Dyspepsia Huynh Giao Ly,*,a Nathalie Weltens,*,a Jan Tack,*,b and Lukas Van Oudenhove*,‡,b *Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium; ‡Psychiatry, University Psychiatric Centre KU Leuven, University Hospitals Leuven, Leuven, Belgium BACKGROUND & AIMS:
Functional dyspepsia (FD) is associated with impaired gastric accommodation, as well as gastric hypersensitivity, delayed emptying, and psychosocial comorbidities. In healthy people, acute anxiety impairs gastric accommodation, measured as the average increase in gastric volume after a meal over 1 hour. This measurement approach does not address the complex time course of the gastric accommodation response to a meal. We modeled gastric accommodation in patients with FD as a function of postprandial time, to investigate whether it is associated with psychosocial factors (state anxiety, anxiety disorder, depression) and gastric sensorimotor function (sensitivity, emptying).
METHODS:
We studied gastric sensorimotor function in 259 consecutive patients diagnosed with FD based on Rome II at the University Hospitals Leuven from January 2002 through February 2009. Subjects underwent a gastric barostat and breath test; psychosocial status was assessed by questionnaires. Subjects completed the State-Trait Anxiety Inventory to measure levels of state anxiety immediately before and after gastric barostat analysis. The time course of the accommodation response was analyzed using mixed models. Psychological and sensorimotor variables were added to the model as continuous (state anxiety) or dichotomous (gastric sensitivity and emptying, anxiety disorders, depression) covariates, including their interaction with the time effects.
RESULTS:
In subjects with FD, delayed emptying (b [ 50.3 – 15.9; P [ .002) and lower state anxiety (b [ -1.7 – 0.7; P [ .012) were associated with an upward shift of the accommodation curve. There was a significant interaction between comorbid anxiety disorder and linear (b [ 8.2 – 3.5; P [ .02), quadratic (b [ -0.4 – 0.1; P [ .004), and cubic (b [ 0.005 – 0.002; P [ .002) effects of time: patients with a comorbid anxiety disorder had significantly slower initial increases in gastric volume to a lower maximum, and a slower return to baseline, compared with patients without anxiety disorder. Depression and gastric sensitivity were not associated significantly with gastric accommodation.
CONCLUSIONS:
In patients with FD, state anxiety and comorbid anxiety disorders are associated with impaired accommodation; gastric emptying also is associated with accommodation in these patients. These findings help elucidate the complex interactions between psychological processes and disorders, gastric sensorimotor dysfunction, and symptom reporting in patients with FD.
Keywords: Psychology; Postprandial Distress; Epigastric Pain; Functional Gastrointestinal Disorders.
unctional dyspepsia (FD) is defined by Rome III criteria as the presence of symptoms thought to originate in the gastroduodenal region in the absence of structural or metabolic disease that explains these symptoms.1 FD is a syndrome with a multifactorial etiology and pathogenesis that likely results from interactions between biological, psychological, and social factors.2–4 First, FD is associated with gastric sensorimotor dysfunction (impaired gastric accommodation to a meal, hypersensitivity to gastric distension, and delayed
F
a
Authors share co-first authorship. bAuthors share co-senior authorship.
Abbreviations used in this paper: ANS, autonomic nervous system; DSS, dyspepsia symptom severity; EPS, epigastric pain syndrome; FD, functional dyspepsia; GI, gastrointestinal; HC, healthy control; PDS, postprandial distress syndrome. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.03.032
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Ly et al
Clinical Gastroenterology and Hepatology Vol.
gastric emptying).4 Second, FD is associated with psychological status alterations (including depressive and anxiety disorders comorbidity).3 Gastric accommodation is a vago-vagal reflex initiated by the arrival of nutrients in the stomach and duodenum and resulting in fundus relaxation (decreased proximal stomach tone), which creates storage capacity for food without pressure increase, thereby enabling the gastric fundus to exert its reservoir function.5 Gastric accommodation commonly is measured using a gastric barostat, and quantified as the difference in intraballoon volume 30 minutes before and 60 minutes after a standardized liquid meal at fixed intraballoon pressure.5 Based on this quantification method, approximately 40% of FD patients have impaired accommodation,5 which has been associated consistently with the postprandial distress symptoms (postprandial fullness, early satiation) of the FD syndrome.2,5 However, this approach ignores the complex time course of the gastric accommodation response, which may result in low statistical power to detect differences between groups or relationships with other relevant etiopathogenetic factors within the heterogeneous FD group. Even without taking these methodologic issues into consideration, research on how other gastric sensorimotor processes and psychosocial comorbidity may be associated with gastric accommodation in FD is virtually nonexistent. However, we previously showed that experimentally induced anxiety significantly impairs gastric accommodation in healthy volunteers, providing proof of concept for central influences on this vago-vagal reflex.6 Therefore, our primary aim was to model the time course of the gastric accommodation response and use this approach to investigate the putative association between gastric accommodation and other key gastric sensorimotor functions (sensitivity, emptying) as well as psychosocial status (state anxiety, comorbid depressive and anxiety disorders). Based on our study in healthy volunteers,6 we hypothesized an association between increasing state anxiety as well as the presence of comorbid anxiety disorders and impaired accommodation (downward shift or lower maximum of the initial postprandial volume increase). Given the lack of prior evidence, no specific a priori hypotheses were formulated for gastric sensitivity, emptying, and presence of comorbid depressive disorder. Our secondary aim was to apply this analysis method to confirm differences in gastric accommodation between healthy controls and FD patients, and an association between postprandial distress symptom levels and impaired accommodation.
Methods Participants Consecutive Dutch-speaking Rome II FD patients with a recent diagnosis (either at their visit to the general
-,
No.
-
gastrointestinal [GI] or GI motility clinic at the University Hospitals Leuven, or at a recent secondary care gastroenterologist visit that lead to referral to our center) were recruited between January 2002 and February 2009. The patient sample of the present study partially overlapped with recent studies from our group.7–9 However, the hypotheses tested in the present study were novel and the results have not been reported elsewhere. Healthy volunteers who participated in gastric barostat studies in which no drugs were administered were used as controls. Details on patients and healthy controls are provided in the Supplementary Methods section.
Gastric Barostat Protocol Gastric sensitivity to distension and gastric accommodation were studied using a gastric barostat. Details are provided in the Supplementary Methods section.
Gastric Emptying Measurement Gastric half-emptying time for solids was calculated using the 14C octanoic acid breath test. The validated cutoff time of 109 minutes was used to define delayed emptying.10
Psychometric Questionnaires On the day of the barostat investigation, FD patients filled out the following self-report questionnaires. Dyspepsia Symptom Severity Scale. The severity of dyspeptic symptoms was evaluated using the Dyspepsia Symptom Severity (DSS) scale, consisting of Likert scales (range, 0–3: absent, mild, moderate, or severe) on the intensity of 9 dyspeptic symptoms during the past 3 months. The DSS is calculated as the sum of all 9 items.11 Because patient recruitment started years before the introduction of the Rome III criteria in 2006, no data on the subdivision of FD in the Epigastric Pain Syndrome (EPS) and/or Postprandial Distress Syndrome (PDS) are available. However, to test the association between the time course of the accommodation response and EPS and PDS symptom levels, EPS symptom severity was quantified by calculating the sum of the epigastric pain and epigastric burning items of the DSS; PDS symptom severity was calculated as the sum of the postprandial fullness and early satiation items. For analysis purposes, the resulting ordinal variables (0–6) were dichotomized by median split. State-Trait Anxiety Inventory, state scale. The state scale of the State-Trait Anxiety Inventory12,13 was filled out twice, immediately before and after the barostat investigation (with the latter rating referring retrospectively to the period during the barostat investigation).
FLA 5.2.0 DTD YJCGH54242_proof 28 April 2015 9:36 pm ce DVC
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175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
-
Anxiety and Accommodation in FD
The mean of these 2 scores was used as a measure for state anxiety during the investigation. Patient Health Questionnaire. The depression and anxiety disorder modules of the Patient Health Questionnaire were completed to screen for comorbid major depressive disorder and anxiety disorders,14 using their validated algorithms.15
Statistical Analysis SAS 9.4 (SAS Institute, Cary, NC) was used to analyze the data, which are expressed as means standard error. Significance was set at a P value of .05 (P < .10 represents a trend). To analyze the time course of the accommodation response, the intraballoon volume data recorded by the barostat device first were divided into 5-minute time bins by averaging the data within each time bin. Next, the average preprandial volume (over all 6 preprandial 5-minute time bins) was subtracted from the volume in each of the 12 postprandial time bins, resulting in a value reflecting volume increase compared with the average preprandial volume for each of these postprandial time bins. The resulting change in volume variable was used as the dependent variable in linear mixed-model analyses with linear, quadratic, cubic, and fourth-order effects of time as continuous independent variables. To test the putative association of sensorimotor and psychosocial variables with the time course of the accommodation response, main effects for the respective independent variables (either continuous or categoric) as well as their interactions with the time effects were added to the model. Details are provided in the Supplementary Methods section.
3 Q1
Table 1. Descriptive Patients Characteristics
Patient characteristic
N (%) Mean SD or positive/above median (IQR) cut-off level
Q25
Gastric sensorimotor function Gastric discomfort threshold 9.9 3.6 mm Hg 108 (42.3%)a Gastric half-emptying time 90.9 53.5 min 36/173 (20.8%)b solids Psychological state State anxiety (STAI) 42.3 8.9 Depression (PHQ-9) 8.4 5.2 76 (29.3%) Anxiety disorder (PHQ) N/A 30 (12.4%) Dyspepsia symptoms Dyspepsia symptom severity 13.4 4.8 Postprandial distress 4 (3–4) symptoms Epigastric pain symptoms 2 (2–4) Comorbid irritable bowel 142 (56.8%) syndrome
PHQ, Patient Health Questionnaire; STAI, State-Trait Anxiety Inventory. a Hypersensitive patients. b Patients with delayed emptying, emptying data were available only in a subgroup (n ¼ 173).
postprandial volume increase), with the quadratic effect representing the turn around the maximum volume increase of the accommodation response and the higherorder effects mostly corresponding to the decrease in volume toward the end of the 1-hour postprandial period. Healthy controls. A similarly parameterized model including significant linear (b ¼ 43.87 3.74; P < .0001), quadratic (b ¼ -2.33 0.24; P < .0001), cubic (b ¼ 0.047 0.0059; P < .0001), and fourth-order (b ¼ -0.00033 0.00005; P < .0001) effects of time, which also fitted the HC data best.
Q18
Results Participants Table 1 shows relevant patient characteristics. Supplementary Figure 1 shows a patient flowchart; details are provided in the Supplementary Methods section. Forty-six historical healthy controls (HCs) (18 women [39%]; mean age, 24.1 3.6 y) were included. Both sex (c2[1] ¼ 24.25; P
Clinical Gastroenterology and Hepatology 2015;-:-–-
1 2 3 4 5 6 7 8 9 10 Q28 11 12Q2Q3 13 14 15 Q10 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49Q11Q13Q12 50 51 52 53 54 55 56 57 58
Acute Anxiety and Anxiety Disorders Are Associated With Impaired Gastric Accommodation in Patients With Functional Dyspepsia Huynh Giao Ly,*,a Nathalie Weltens,*,a Jan Tack,*,b and Lukas Van Oudenhove*,‡,b *Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium; ‡Psychiatry, University Psychiatric Centre KU Leuven, University Hospitals Leuven, Leuven, Belgium BACKGROUND & AIMS:
Functional dyspepsia (FD) is associated with impaired gastric accommodation, as well as gastric hypersensitivity, delayed emptying, and psychosocial comorbidities. In healthy people, acute anxiety impairs gastric accommodation, measured as the average increase in gastric volume after a meal over 1 hour. This measurement approach does not address the complex time course of the gastric accommodation response to a meal. We modeled gastric accommodation in patients with FD as a function of postprandial time, to investigate whether it is associated with psychosocial factors (state anxiety, anxiety disorder, depression) and gastric sensorimotor function (sensitivity, emptying).
METHODS:
We studied gastric sensorimotor function in 259 consecutive patients diagnosed with FD based on Rome II at the University Hospitals Leuven from January 2002 through February 2009. Subjects underwent a gastric barostat and breath test; psychosocial status was assessed by questionnaires. Subjects completed the State-Trait Anxiety Inventory to measure levels of state anxiety immediately before and after gastric barostat analysis. The time course of the accommodation response was analyzed using mixed models. Psychological and sensorimotor variables were added to the model as continuous (state anxiety) or dichotomous (gastric sensitivity and emptying, anxiety disorders, depression) covariates, including their interaction with the time effects.
RESULTS:
In subjects with FD, delayed emptying (b [ 50.3 – 15.9; P [ .002) and lower state anxiety (b [ -1.7 – 0.7; P [ .012) were associated with an upward shift of the accommodation curve. There was a significant interaction between comorbid anxiety disorder and linear (b [ 8.2 – 3.5; P [ .02), quadratic (b [ -0.4 – 0.1; P [ .004), and cubic (b [ 0.005 – 0.002; P [ .002) effects of time: patients with a comorbid anxiety disorder had significantly slower initial increases in gastric volume to a lower maximum, and a slower return to baseline, compared with patients without anxiety disorder. Depression and gastric sensitivity were not associated significantly with gastric accommodation.
CONCLUSIONS:
In patients with FD, state anxiety and comorbid anxiety disorders are associated with impaired accommodation; gastric emptying also is associated with accommodation in these patients. These findings help elucidate the complex interactions between psychological processes and disorders, gastric sensorimotor dysfunction, and symptom reporting in patients with FD.
Keywords: Psychology; Postprandial Distress; Epigastric Pain; Functional Gastrointestinal Disorders.
unctional dyspepsia (FD) is defined by Rome III criteria as the presence of symptoms thought to originate in the gastroduodenal region in the absence of structural or metabolic disease that explains these symptoms.1 FD is a syndrome with a multifactorial etiology and pathogenesis that likely results from interactions between biological, psychological, and social factors.2–4 First, FD is associated with gastric sensorimotor dysfunction (impaired gastric accommodation to a meal, hypersensitivity to gastric distension, and delayed
F
a
Authors share co-first authorship. bAuthors share co-senior authorship.
Abbreviations used in this paper: ANS, autonomic nervous system; DSS, dyspepsia symptom severity; EPS, epigastric pain syndrome; FD, functional dyspepsia; GI, gastrointestinal; HC, healthy control; PDS, postprandial distress syndrome. © 2015 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2015.03.032
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Ly et al
Clinical Gastroenterology and Hepatology Vol.
gastric emptying).4 Second, FD is associated with psychological status alterations (including depressive and anxiety disorders comorbidity).3 Gastric accommodation is a vago-vagal reflex initiated by the arrival of nutrients in the stomach and duodenum and resulting in fundus relaxation (decreased proximal stomach tone), which creates storage capacity for food without pressure increase, thereby enabling the gastric fundus to exert its reservoir function.5 Gastric accommodation commonly is measured using a gastric barostat, and quantified as the difference in intraballoon volume 30 minutes before and 60 minutes after a standardized liquid meal at fixed intraballoon pressure.5 Based on this quantification method, approximately 40% of FD patients have impaired accommodation,5 which has been associated consistently with the postprandial distress symptoms (postprandial fullness, early satiation) of the FD syndrome.2,5 However, this approach ignores the complex time course of the gastric accommodation response, which may result in low statistical power to detect differences between groups or relationships with other relevant etiopathogenetic factors within the heterogeneous FD group. Even without taking these methodologic issues into consideration, research on how other gastric sensorimotor processes and psychosocial comorbidity may be associated with gastric accommodation in FD is virtually nonexistent. However, we previously showed that experimentally induced anxiety significantly impairs gastric accommodation in healthy volunteers, providing proof of concept for central influences on this vago-vagal reflex.6 Therefore, our primary aim was to model the time course of the gastric accommodation response and use this approach to investigate the putative association between gastric accommodation and other key gastric sensorimotor functions (sensitivity, emptying) as well as psychosocial status (state anxiety, comorbid depressive and anxiety disorders). Based on our study in healthy volunteers,6 we hypothesized an association between increasing state anxiety as well as the presence of comorbid anxiety disorders and impaired accommodation (downward shift or lower maximum of the initial postprandial volume increase). Given the lack of prior evidence, no specific a priori hypotheses were formulated for gastric sensitivity, emptying, and presence of comorbid depressive disorder. Our secondary aim was to apply this analysis method to confirm differences in gastric accommodation between healthy controls and FD patients, and an association between postprandial distress symptom levels and impaired accommodation.
Methods Participants Consecutive Dutch-speaking Rome II FD patients with a recent diagnosis (either at their visit to the general
-,
No.
-
gastrointestinal [GI] or GI motility clinic at the University Hospitals Leuven, or at a recent secondary care gastroenterologist visit that lead to referral to our center) were recruited between January 2002 and February 2009. The patient sample of the present study partially overlapped with recent studies from our group.7–9 However, the hypotheses tested in the present study were novel and the results have not been reported elsewhere. Healthy volunteers who participated in gastric barostat studies in which no drugs were administered were used as controls. Details on patients and healthy controls are provided in the Supplementary Methods section.
Gastric Barostat Protocol Gastric sensitivity to distension and gastric accommodation were studied using a gastric barostat. Details are provided in the Supplementary Methods section.
Gastric Emptying Measurement Gastric half-emptying time for solids was calculated using the 14C octanoic acid breath test. The validated cutoff time of 109 minutes was used to define delayed emptying.10
Psychometric Questionnaires On the day of the barostat investigation, FD patients filled out the following self-report questionnaires. Dyspepsia Symptom Severity Scale. The severity of dyspeptic symptoms was evaluated using the Dyspepsia Symptom Severity (DSS) scale, consisting of Likert scales (range, 0–3: absent, mild, moderate, or severe) on the intensity of 9 dyspeptic symptoms during the past 3 months. The DSS is calculated as the sum of all 9 items.11 Because patient recruitment started years before the introduction of the Rome III criteria in 2006, no data on the subdivision of FD in the Epigastric Pain Syndrome (EPS) and/or Postprandial Distress Syndrome (PDS) are available. However, to test the association between the time course of the accommodation response and EPS and PDS symptom levels, EPS symptom severity was quantified by calculating the sum of the epigastric pain and epigastric burning items of the DSS; PDS symptom severity was calculated as the sum of the postprandial fullness and early satiation items. For analysis purposes, the resulting ordinal variables (0–6) were dichotomized by median split. State-Trait Anxiety Inventory, state scale. The state scale of the State-Trait Anxiety Inventory12,13 was filled out twice, immediately before and after the barostat investigation (with the latter rating referring retrospectively to the period during the barostat investigation).
FLA 5.2.0 DTD YJCGH54242_proof 28 April 2015 9:36 pm ce DVC
Q14
175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232
-
Anxiety and Accommodation in FD
The mean of these 2 scores was used as a measure for state anxiety during the investigation. Patient Health Questionnaire. The depression and anxiety disorder modules of the Patient Health Questionnaire were completed to screen for comorbid major depressive disorder and anxiety disorders,14 using their validated algorithms.15
Statistical Analysis SAS 9.4 (SAS Institute, Cary, NC) was used to analyze the data, which are expressed as means standard error. Significance was set at a P value of .05 (P < .10 represents a trend). To analyze the time course of the accommodation response, the intraballoon volume data recorded by the barostat device first were divided into 5-minute time bins by averaging the data within each time bin. Next, the average preprandial volume (over all 6 preprandial 5-minute time bins) was subtracted from the volume in each of the 12 postprandial time bins, resulting in a value reflecting volume increase compared with the average preprandial volume for each of these postprandial time bins. The resulting change in volume variable was used as the dependent variable in linear mixed-model analyses with linear, quadratic, cubic, and fourth-order effects of time as continuous independent variables. To test the putative association of sensorimotor and psychosocial variables with the time course of the accommodation response, main effects for the respective independent variables (either continuous or categoric) as well as their interactions with the time effects were added to the model. Details are provided in the Supplementary Methods section.
3 Q1
Table 1. Descriptive Patients Characteristics
Patient characteristic
N (%) Mean SD or positive/above median (IQR) cut-off level
Q25
Gastric sensorimotor function Gastric discomfort threshold 9.9 3.6 mm Hg 108 (42.3%)a Gastric half-emptying time 90.9 53.5 min 36/173 (20.8%)b solids Psychological state State anxiety (STAI) 42.3 8.9 Depression (PHQ-9) 8.4 5.2 76 (29.3%) Anxiety disorder (PHQ) N/A 30 (12.4%) Dyspepsia symptoms Dyspepsia symptom severity 13.4 4.8 Postprandial distress 4 (3–4) symptoms Epigastric pain symptoms 2 (2–4) Comorbid irritable bowel 142 (56.8%) syndrome
PHQ, Patient Health Questionnaire; STAI, State-Trait Anxiety Inventory. a Hypersensitive patients. b Patients with delayed emptying, emptying data were available only in a subgroup (n ¼ 173).
postprandial volume increase), with the quadratic effect representing the turn around the maximum volume increase of the accommodation response and the higherorder effects mostly corresponding to the decrease in volume toward the end of the 1-hour postprandial period. Healthy controls. A similarly parameterized model including significant linear (b ¼ 43.87 3.74; P < .0001), quadratic (b ¼ -2.33 0.24; P < .0001), cubic (b ¼ 0.047 0.0059; P < .0001), and fourth-order (b ¼ -0.00033 0.00005; P < .0001) effects of time, which also fitted the HC data best.
Q18
Results Participants Table 1 shows relevant patient characteristics. Supplementary Figure 1 shows a patient flowchart; details are provided in the Supplementary Methods section. Forty-six historical healthy controls (HCs) (18 women [39%]; mean age, 24.1 3.6 y) were included. Both sex (c2[1] ¼ 24.25; P
