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© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

INTRODUCTION Dyspepsia is a syndrome that has been defi ned by expert consensus

( 1 ). Th e most widely used criteria are the Rome criteria, which are

in their third iteration. Th e Rome criteria were developed prima-

rily for research purposes; however, regulatory agencies have used

them to set criteria for regulatory trials. Th ese criteria therefore

have an important impact on clinical practice. Symptoms of dys-

pepsia are widely prevalent in the community. By some estimates,

10 % of all patients presenting for endoscopy for upper gastrointes-

tinal symptoms have dyspepsia as defi ned by the Rome III criteria

as the cause of their symptoms ( 2 ). Despite extensive research into

the pathophysiology and treatment of dyspepsia, a single unify-

ing mechanism to explain the multiple symptoms has been elusive

and, despite extensive research into pharmacological targets, many

countries (e.g., the USA and the European Union countries) have

no pharmacological agents approved to treat this condition.

Th e Rome criteria have changed over the years: Rome II defi ned

functional dyspepsia as pain or discomfort centered in the upper

abdomen and did not give emphasis to meal-related symptoms

( 3 ). For Rome III, functional dyspepsia is de-emphasized as an

entity and replaced with two new diagnostic categories under the

dyspepsia symptom complex umbrella: postprandial distress syn-

drome (PDS) and epigastric pain syndrome (EPS) ( 4 ). Th e syn-

dromes are based on data from factor analytic studies in the general

population and in patients with dyspeptic symptoms, which dis-

tinguished between diff erent symptom clusters of meal-induced

and meal-unrelated symptoms ( 4 ). Diagnostic criteria for PDS are

bothersome postprandial fullness and / or early satiety, and those

for EPS are epigastric pain and / or epigastric burning; there should

be no evidence of structural disease, including at upper endoscopy,

which is likely to explain the symptoms. Th e distinction between

PDS and EPS is thought to be pathophysiologically and clinically

Symptom Overlap Between Postprandial Distress and Epigastric Pain Syndromes of the Rome III Dyspepsia Classifi cation Nimish Vakil , MD, FACG 1 , Katarina Halling , MSc 2 , Lis Ohlsson , MSc 2 and B ö rje Wernersson , BSc 2

OBJECTIVES: The Rome III criteria for functional dyspepsia recognize two distinct subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). The aim of this exploratory analysis was to evaluate the Rome III criteria and the validity of the PDS / EPS subgrouping in primary care patients with upper gastrointestinal symptoms.

METHODS: Primary care patients with frequent upper gastrointestinal symptoms included in the Diamond study (NCT00291746) underwent esophageal endoscopy and 24-h pH-metry. Gastroesophageal refl ux dis-ease (GERD) was defi ned as the presence of at least one of the following: refl ux esophagitis, patho-logical esophageal acid exposure, positive symptom association probability (SAP >– 95 % ) for associa-tion of symptoms with acid refl ux. Functional dyspepsia was defi ned by the absence of GERD and peptic ulcer disease on investigation. PDS and / or EPS were diagnosed according to Rome III criteria.

RESULTS: In total, 138 patients (41 % ) had upper gastrointestinal symptoms with normal endoscopy, pH-metry, and SAP results, consistent with the presence of functional dyspepsia. Of these patients, 130 (94 % ) met criteria for PDS and / or EPS: 13 (10 % ) had PDS alone, 31 (24 % ) had EPS alone, and 86 (66 % ) met criteria for both PDS and EPS.

CONCLUSIONS: PDS and EPS overlap in the majority of patients with functional dyspepsia. The value of dividing functional dyspepsia into the subgroups of PDS and EPS is thus questionable. A new approach to classifying functional dyspepsia is needed.

Am J Gastroenterol 2013; 108:767–774; doi: 10.1038/ajg.2013.89; published online 9 April 2013

1 University of Wisconsin, School of Medicine and Public Health , Madison , Wisconsin , USA ; 2 AstraZeneca R & D , M ö lndal , Sweden . Correspondence: Nimish Vakil, MD, FACG , University of Wisconsin, School of Medicine and Public Health, Aurora Summit Hospital , 36500 Aurora Drive, Summit, Wisconsin 53066 , USA . E-mail: [email protected] Received 11 December 2012; accepted 14 January 2013

see related editorial on page 775

The American Journal of GASTROENTEROLOGY VOLUME 108 | MAY 2013 www.amjgastro.com

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relevant, with the possibility that these two syndromes might have

diff ering responses to medication, thus allowing a more rational

approach to drug discovery and development ( 4 ). Predominant

symptom assessment was also abandoned in Rome III because of

the poor predictive value of the predominant symptom ( 5 ).

Th e Rome III criteria recommend that any overlap of gastro-

esophageal refl ux disease (GERD) with PDS or EPS needs to be

carefully considered in clinical practice and experimental trials

( 4 ). GERD is typically identifi ed based on symptoms or endoscopy.

However, primary care patients with upper gastrointestinal symp-

toms oft en present with multiple upper gastrointestinal symptoms,

making symptom-based diagnoses in these patients diffi cult in

practice ( 6 ). Some studies in specialty clinics have suggested that

20 % of patients diagnosed with functional dyspepsia aft er endos-

copy and symptom assessments may also have GERD by pH-metry,

illustrating the diffi culties facing the clinician ( 7,8 ).

Validation of the Rome III criteria dyspepsia subgroups of PDS

and EPS is important before they are widely used in clinical and

regulatory trials. Th e principal aim of this exploratory analysis

was to evaluate the Rome III criteria for functional dyspepsia and

PDS / EPS in a group of primary care patients with frequent upper

gastrointestinal symptoms, with specifi c regard to the degree of

symptom overlap between PDS and EPS. A secondary aim was to

determine the proportion of patients with GERD who met the crite-

ria for PDS and / or EPS, to determine if these syndromes have value

in separating GERD and functional dyspepsia in clinical practice.

METHODS Study population Th e Diamond study (ClinicalTrials. gov number NCT00291746) was

conducted in Western Europe and Canada, and recruited primary

care patients aged 18 – 79 years who presented with upper gastroin-

testinal symptoms ( 9 ). To be included in the study, individuals had

to have a history of symptoms occurring at least twice per week

for at least 4 weeks before presentation, and symptoms of at least

mild severity on at least 3 days during the 7 days before study entry.

Major exclusion criteria were upper gastrointestinal endoscopy dur-

ing the year before the study, previous anti-refl ux surgery or surgery

for peptic ulcer or other gastrointestinal resections, use of proton

pump inhibitors in the 2 months before study entry, daily use of ace-

tylsalicylic acid (>165 mg / day) or non-steroidal anti-infl ammatory

drugs (any dose), and “ alarm ” features. Patients with Los Angeles

classifi cation grade D refl ux esophagitis or other contraindications

to attachment of the pH probe for esophageal pH monitoring were

excluded from the Diamond study because of safety concerns.

Study investigations All patients completed the Refl ux Disease Questionnaire (RDQ),

were assessed with regard to a pre-specifi ed list of 19 upper gas-

trointestinal symptoms, and underwent upper gastrointestinal

endoscopy and 48-h esophageal pH recording.

RDQ . Th e RDQ is a 12-item patient-reported outcome instru-

ment that has been psychometrically validated for evaluative and

diagnostic purposes ( 6,9 – 11 ). Six symptom descriptors covering

heartburn, regurgitation, and upper abdominal pain and burning

are assessed separately for their frequency and severity in the pre-

vious 7 days, using a six-point Likert scale. Th e RDQ was included

in the Diamond study to assess its diagnostic accuracy for GERD

as defi ned by investigation ( 9 ).

Symptom assessment . At enrolment, patients were assessed

by the respective study physicians about the presence in the

Primary care patients withfrequent upper

gastrointestinal symptoms

Peptic ulcer disease

GERD FD

FD without PDSGERD without PDS

GERD with PDSalone (without

EPS)

GERD with PDSand EPS

GERD with EPSalone

(without PDS)

FD with PDSalone (without

EPS)

FD with PDSand EPS

FD with EPSalone

(without PDS)

and/or EPSand/or EPS

N = 336

n = 9

n = 189 n = 138

n = 8n = 30

n = 36 n = 81 n = 42 n = 13n = 86

n = 31

Figure 1 . Flow chart showing diagnoses of peptic ulcer disease, gastroesophageal refl ux disease (GERD), functional dyspepsia (FD), epigastric pain syndrome (EPS), and postprandial distress syndrome (PDS).


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Rome III: Symptom Overlap Between PDS and EPS

previous 7 days of the following 19 pre-specifi ed upper gas-

trointestinal symptoms, based on a structured symptom list and

described in lay language: bloating, central chest pain, central

upper abdominal discomfort, central upper abdominal pain, dys-

phagia, early satiety, generalized upper abdominal discomfort,

generalized upper abdominal pain, heartburn, nausea, left -sided

upper abdominal discomfort, left -sided upper abdominal pain,

pancreatic pain, postprandial fullness, regurgitation, right-sided

upper abdominal discomfort, right-sided upper abdominal pain,

and vomiting ( 9 ). Th e recall period for the 19 symptoms was

1 week.

Upper gastrointestinal endoscopy . All patients underwent upper

gastrointestinal endoscopy, performed by gastroenterologists at

specialist centers. Refl ux esophagitis and other endoscopic abnor-

malities were noted; refl ux esophagitis was graded according to

the Los Angeles classifi cation.

Esophageal pH monitoring . All patients underwent esophageal

pH monitoring. A wireless pH-monitoring capsule (Bravo; Given

Imaging, Yoqneam, Israel) was anchored in the distal esophagus,

6 cm above the endoscopically measured squamocolumnar junc-

tion, and esophageal pH was monitored for 48 h. Esophageal acid

exposure, including symptom association probability (SAP) ( 12 ),

was analyzed over 24 h from midnight on the fi rst day of pH cap-

sule placement, in order to standardize the time window for pH

data analysis.

Symptom event monitoring during esophageal pH measurement .

Patients used a special diary card to record the occurrence and

severity (mild, moderate, severe) of the two most bothersome

symptoms that they had selected at enrolment from the list of

19 pre-specifi ed upper gastrointestinal symptoms. Th e timing of

these symptoms during pH metry was recorded by event markers.

Th e SAP was determined over 24 h from midnight on the day the

pH capsule was placed.

Diagnostic criteria GERD . GERD was diagnosed when at least one of the following

criteria was present:

1. Refl ux esophagitis on endoscopy (Los Angeles classifi cation

grades A – C).

Table 1 . Demographics and baseline characteristics of patients with functional dyspepsia or GERD

Baseline characteristic

Functional dyspepsia ( n =138)

GERD ( n =189) P value

Sex

Male 42 (30.4) 106 (56.1) < 0.0001

Female 96 (69.6) 83 (43.9)

Age, years

Mean 45.8 48.0 0.1550

s.d. 14.7 13.4

Range 18 – 74 18 – 76

BMI, kg / m 2

Mean 25.4 27.5 < 0.0001

s.d. 4.5 4.5

Range 16 – 38 16 – 46

Hiatal hernia

No 99 (71.7) 100 (52.9) 0.0006

Yes 39 (28.3) 89 (47.1)

H. pylori status a

Negative 107 (77.5) 147 (77.8) 0.9168

Positive 29 (21.0) 41 (21.7)

BMI, body mass index; GERD, gastroesophageal refl ux disease; H. pylori , Helicobacter pylori . a H. pylori status was not known in two patients with functional dyspepsia and one patient with GERD. Data are presented as n ( % ) unless otherwise indicated. Analysis of variance was used to test the equality of means in continuous variables and the Mantel – Haenszel test was used for proportions.

Table 2 . Demographics and baseline characteristics of patients with PDS alone, EPS alone, and PDS + EPS in the functional dyspepsia group


PDS alone ( n =13)

EPS alone ( n =31)

PDS + EPS ( n =86) P value

Sex

Male 4 (30.8) 10 (32.3) 24 (27.9) 0.6495

Female 9 (69.2) 21 (67.7) 62 (72.1)

Age, years

Mean 42.9 48.9 44.6 0.3172

s.d. 15.1 12.9 15.3

Range 18 – 65 24 – 72 18 – 72

BMI, kg / m 2

Mean 25.5 25.5 25.4 0.9890

s.d. 4.1 4.3 4.7

Range 20 – 35 18 – 36 16 – 38

Hiatal hernia

No 13 (100.0) 21 (67.7) 59 (68.6) 0.2398

Yes 0 (0.0) 10 (32.3) 27 (31.4)

H. pylori status a

Negative 7 (53.8) 24 (77.4) 69 (80.2) 0.1952

Positive 6 (46.2) 6 (19.4) 16 (18.6)

BMI, body mass index; EPS, epigastric pain syndrome; H. pylori , Helicobacter pylori ; PDS, postprandial distress syndrome. a H. pylori status was not known in one patient with EPS alone and one patient with PDS + EPS. Data are presented as n ( % ) unless otherwise indicated. Analysis of variance was used to test the equality of means in continuous variables and the Mantel – Haenszel test was used for proportions.


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Vakil et al.

2. Pathological distal esophageal acid exposure (esophageal

pH < 4 for >5.5 % of the time during 24 h).

3. Positive SAP ( ≥ 95 % ) for association of symptoms with acid

refl ux.

Functional dyspepsia . Patients meeting the study inclusion cri-

teria were defi ned as having functional dyspepsia if they did not

meet the diagnostic criteria for GERD (outlined above) or peptic

ulcer disease on investigation.

PDS and EPS . PDS was defi ned as postprandial fullness ( “ feeling

full even long aft er you have stopped eating ” ) and / or early satiety

( “ feeling full shortly aft er you have started eating ” ) of at least mild

severity and with a duration of at least 4 weeks. PDS symptom

data were obtained from the list of pre-specifi ed upper gastroin-

testinal symptoms.

EPS was defi ned as epigastric pain ( “ a pain in the center of the

upper stomach) and / or epigastric burning ( “ a burning feeling in

the center of the upper stomach ” ) of at least moderate severity and

occurring at least once per week. EPS symptom data were obtained

from the RDQ.

Statistical analyses Demographics and baseline characteristics were compared

between patients with functional dyspepsia and patients with

GERD, and between the three syndrome subgroups (PDS alone;

EPS alone; concomitant PDS and EPS). Analysis of variance was

used for continuous variables. For proportions, Fisher ’ s exact test

was used for the comparison between the functional dyspepsia

vs. GERD groups and the Mantel – Haenszel test was used for the

comparison between the three syndrome subgroups. Th e Mantel –

Haenszel test was used to investigate the prevalence of the pre-

specifi ed 19 upper gastrointestinal symptoms in the three syn-

drome subgroups and the distribution of the three syndrome

subgroups in patients with a symptom duration of 6 months or

longer compared with a duration of < 6 months. Fisher ’ s exact test

was used to compare the frequency of heartburn and / or regur-

gitation as the predominant (most or second most bothersome)

symptom between patients with GERD and patients with func-

tional dyspepsia, and between patients with or without concomi-

tant PDS and EPS. A logistic regression analysis was performed to

explore the possible association between PDS and EPS. Th e prob-

ability of functional dyspepsia vs. GERD was modeled and odds

ratios with 95 % confi dence intervals were estimated for each of

the explanatory variables in the model.

RESULTS Diagnoses Of the 336 primary care patients who reported upper gastrointes-

tinal symptoms on physician assessment, 9 received a diagnosis of

peptic ulcer and were not included in further analyses, and 189 of

the remaining patients were diagnosed with GERD on investiga-

tion. Of these, 159 (84 % ) also met criteria for PDS and / or EPS: 36

(19 % ) had PDS alone, 42 (22 % ) had EPS alone, and 81 (43 % ) met

criteria for both PDS and EPS.

Table 3 . Demographics and baseline characteristics of patients with PDS alone, EPS alone, and PDS + EPS in the GERD group


PDS alone ( n =36)

EPS alone ( n =42)

PDS + EPS ( n =81) P value

Sex

Male 18 (50.0) 23 (54.8) 42 (51.9) 0.9562

Female 18 (50.0) 19 (45.2) 39 (48.1)

Age, years

Mean 48.5 49.6 46.8 0.5196

s.d. 15.6 13.2 12.8

Range 19 – 75 18 – 74 19 – 71

BMI, kg / m 2

Mean 26.7 27.5 27.5 0.6269

s.d. 3.9 4.3 4.5

Range 21 – 36 20 – 40 16 – 39

Hiatal hernia

No 22 (61.1) 15 (35.7) 47 (58.0) 0.2523

Yes 14 (38.9) 27 (64.3) 34 (42.0)

H. pylori status

Negative 29 (80.6) 32 (76.2) 65 (80.2) 0.7822

Positive 7 (19.4) 10 (23.8) 16 (19.8)

BMI, body mass index; EPS, epigastric pain syndrome; GERD, gastroesophageal refl ux disease; H. pylori , Helicobacter pylori ; PDS, postprandial distress syndrome.Data are presented as n ( % ) unless otherwise indicated. Analysis of variance was used to test the equality of means in continuous variables and the Mantel – Haenszel test was used for proportions.

100

90

80

70

60

50

40

30

20

10

0

34.4

Patients GERD (n = 189)

30.4

43.5

21.726.1

43.9

Number of upper gastrointestinal symptoms

1–5 6–10 11–19

Pro

port

ion

of p

atei

nts

(%)

Patients with functional dyspepsia (n = 138)

Figure 2 . Number of upper gastrointestinal symptoms in patients with functional dyspepsia or gastroesophageal refl ux disease (GERD).


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Symptom number and frequency Th e mean number of reported upper gastrointestinal symptoms per

patient was 8.2. (s.d.: 4.0) in patients with functional dyspepsia and

7.7 (s.d.: 3.6) in patients with GERD ( P = 0.2884). Overall, 69.6 % of

patients with functional dyspepsia and 65.6 % of those with GERD

reported six or more upper gastrointestinal symptoms ( Figure 2 ).

Patients with PDS alone, EPS alone, or concomitant PDS and

EPS had similar frequencies of most of the reported upper gas-

trointestinal symptoms, both in functional dyspepsia ( Table 4 ) and

in GERD ( Table 5 ). In the PDS group, postprandial fullness was

more frequent than early satiety. Central upper abdominal pain

was more common in the EPS than the PDS group, both in func-

tional dyspepsia and in GERD, whereas central upper abdominal

discomfort was more common in the PDS than the EPS group in

patients with functional dyspepsia, but was slightly more common

in the EPS than the PDS group in patients with GERD.

Heartburn and regurgitation (the typical symptoms of GERD

( 13 )) were present in 76 % and 72 % , respectively, of the 189 patients

with GERD, and 59 % and 54 % , respectively, of the 138 patients with

Th e remaining 138 patients had upper gastrointestinal symp-

toms with normal endoscopy, pH-metry, and SAP results, consist-

ent with the presence of functional dyspepsia. Of these patients,

130 (94 % ) met the criteria for PDS and / or EPS: 13 (10 % ) had PDS

alone, 31 (24 % ) had EPS alone, and 86 (66 % ) met criteria for both

PDS and EPS. Eight patients (6 % ) with functional dyspepsia did

not meet criteria for PDS and / or EPS and were thus not classifi -

able by current criteria. A fl ow chart showing the distribution of

diagnoses of peptic ulcer disease, GERD, functional dyspepsia, and

PDS / EPS is shown in Figure 1 .

Patient demographics Overall, the group of patients with functional dyspepsia had a

higher prevalence of women, a lower mean body mass index and

a lower prevalence of hiatal hernia than the group with GERD

( Table 1 ). Th ere were no statistically signifi cant diff erences in

demographic characteristics between patients with PDS alone,

EPS alone, or both PDS and EPS, neither in the functional dys-

pepsia group ( Table 2 ) nor in the GERD group ( Table 3 ).

Table 4 . Frequency of upper gastrointestinal symptoms in patients with PDS alone, EPS alone, and PDS + EPS in the functional dyspepsia group

Symptom PDS alone ( n =13) n ( % ) EPS alone ( n =31) n ( % ) PDS + EPS ( n =86) n ( % ) P value

Belching 11 (84.6) 15 (48.4) 57 (66.3) 0.0546

Bloating 8 (61.5) 20 (64.5) 73 (84.9) 0.0227

Early satiety 8 (61.5) 0 (0) 66 (76.7) < 0.0001

Postprandial fullness 12 (92.3) 0 (0) 68 (79.1) < 0.0001

Central chest pain 5 (38.5) 12 (38.7) 35 (40.7) 0.9746

Heartburn 7 (53.8) 20 (64.5) 51 (59.3) 0.7857

Regurgitation 9 (69.2) 14 (45.2) 45 (52.3) 0.3481

Dysphagia 1 (7.7) 1 (3.2) 12 (14) 0.2406

Generalized upper abdominal pain

4 (30.8) 16 (51.6) 45 (52.3) 0.3456

Central upper abdominal pain

2 (15.4) 16 (51.6) 68 (79.1) < 0.0001

Left-sided upper abdominal pain

1 (7.7) 6 (19.4) 27 (31.4) 0.1208

Right-sided upper abdominal pain

1 (7.7) 6 (19.4) 23 (26.7) 0.2716

Generalized upper abdominal discomfort

5 (38.5) 11 (35.5) 42 (48.8) 0.3963

Central upper abdominal discomfort

8 (61.5) 11 (35.5) 57 (66.3) 0.0118

Left-sided upper abdominal discomfort

1 (7.7) 6 (19.4) 23 (26.7) 0.2716

Right-sided upper abdominal discomfort

1 (7.7) 7 (22.6) 19 (22.1) 0.4741

Pancreatic pain 3 (23.1) 3 (9.7) 26 (30.2) 0.0755

Nausea 6 (46.2) 15 (48.4) 56 (65.1) 0.1624

Vomiting 3 (23.1) 1 (3.2) 18 (20.9) 0.0663

EPS, epigastric pain syndrome; PDS, postprandial distress syndrome. The Mantel – Haenszel test was used for proportions.


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functional dyspepsia. Heartburn and / or regurgitation were the pre-

dominant symptoms (most or second most bothersome symptoms

reported on physician-administered symptom assessment) in 57 %

of the 159 patients with GERD who had concomitant PDS and / or

EPS, and in 30 % of the 130 patients with functional dyspepsia with

PDS and / or EPS ( P < 0.0001; Table 6 ). Predominant symptoms of

heartburn and regurgitation were not the principal determinant

of whether a patient had PDS or EPS: 39.5 % of patients who met

criteria for both PDS and EPS had symptoms of heartburn and / or

regurgitation ( Table 7 ).

Duration of symptoms, and impact on PDS and EPS Th e duration of the most bothersome upper gastrointestinal symp-

tom was 6 months or longer in 74 % (118 / 159) of patients with

EPS and / or PDS with concomitant GERD and in 61 % (79 / 130) of

those with EPS and / or PDS and functional dyspepsia ( P = 0.0162).

For the second most bothersome upper gastrointestinal symptom,

the duration was 6 months or longer in 74 % (117 / 159) of patients

with EPS and / or PDS with concomitant GERD and in 59 %

(77 / 130) of those with EPS and / or PDS and functional dyspep-

sia. Th ere was no statistical evidence that the frequency pattern

Table 5 . Frequency of upper gastrointestinal symptoms in patients with PDS alone, EPS alone, and PDS + EPS in the GERD group

Symptom PDS alone ( n =13) n ( % ) EPS alone ( n =31) n ( % ) PDS + EPS ( n =86) n ( % ) P value

Belching 28 (77.8) 25 (59.5) 63 (77.8) 0.0748

Bloating 30 (83.3) 30 (71.4) 73 (90.1) 0.0298

Early satiety 21 (58.3) 0 (0) 41 (50.6) 0.0000

Postprandial fullness 31 (86.1) 0 (0) 69 (85.2) 0.0000

Central chest pain 14 (38.9) 15 (35.7) 46 (56.8) 0.0457

Heartburn 24 (66.7) 31 (73.8) 66 (81.5) 0.2068

Regurgitation 24 (66.7) 31 (73.8) 59 (72.8) 0.7447

Dysphagia 9 (25) 7 (16.7) 19 (23.5) 0.6131

Generalized upper abdominal pain 8 (22.2) 13 (31) 39 (48.1) 0.0166

Central upper abdominal pain 14 (38.9) 27 (64.3) 56 (69.1) 0.0075

Left-sided upper abdominal pain 6 (16.7) 6 (14.3) 23 (28.4) 0.1383

Right-sided upper abdominal pain 3 (8.3) 7 (16.7) 17 (21) 0.2445

Generalized upper abdominal discomfort 9 (25) 13 (31) 41 (50.6) 0.0137

Central upper abdominal discomfort 14 (38.9) 19 (45.2) 54 (66.7) 0.0076

Left-sided upper abdominal discomfort 7 (19.4) 4 (9.5) 22 (27.2) 0.0726

Right-sided upper abdominal discomfort 3 (8.3) 5 (11.9) 15 (18.5) 0.3047

Pancreatic pain 4 (11.1) 7 (16.7) 17 (21) 0.4274

Nausea 10 (27.8) 16 (38.1) 44 (54.3) 0.0194

Vomiting 5 (13.9) 5 (11.9) 17 (21) 0.3825

EPS, epigastric pain syndrome; GERD, gastroesophageal refl ux disease; PDS, postprandial distress syndrome. The Mantel – Haenszel test was used for proportions.

Table 6 . Heartburn and / or regurgitation reported as the predominant symptoms (most or second most bothersome symptom) in patients with EPS and / or PDS in the GERD or functional dyspepsia cohort

Diagnosis Heartburn and / or

regurgitation n ( % ) Other n ( % ) P value

GERD with EPS and / or PDS ( n =159)

90 (56.6) 69 (43.4) < 0.0001

Functional dyspepsia with EPS and / or PDS ( n =130)

39 (30.0) 91 (70.0)

EPS, epigastric pain syndrome; GERD, gastroesophageal refl ux disease; PDS, postprandial distress syndrome. Fisher’s exact test was used for proportions.

Table 7 . Heartburn and / or regurgitation reported as the predominant symptoms in patients with or without concomitant PDS and EPS

PDS and EPS Heartburn and / or

regurgitation n ( % ) Other n ( % ) P value

No ( n =160) 89 (55.6) 71 (44.4) 0.0040

Yes ( n =167) 66 (39.5) 101 (60.5)

EPS, epigastric pain syndrome; PDS, postprandial distress syndrome. Fisher’s exact test was used for proportions. Predominant symptoms defi ned as most and / or second most bothersome upper gastrointestinal symptoms.


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or more upper gastrointestinal symptoms. A predominant symp-

tom of heartburn or regurgitation was found more frequently in

GERD than functional dyspepsia, but also occurred frequently in

functional dyspepsia. Th ere was striking overlap between symp-

toms of GERD and functional dyspepsia confi rming previous

descriptions and highlighting the diffi culty in making a clinical

diagnosis in a primary care setting ( 2 ).

Th e Rome III criteria for functional dyspepsia were developed

for research, and are widely used to design clinical trials and regu-

latory studies. Trial designs in functional gastrointestinal dis orders

inevitably infl uence clinical practice, because a drug approval

will carry the same indication as that used in the regulatory trial

design. Th e case defi nition can determine the outcome of a trial,

and a treatment trial may fail if the criteria that defi ne the disease

are poor. For example, effi cacy outcomes from the itopride phase 2

clinical trial ( 14 ) diff ered greatly from those from phase 3 clinical

trials ( 15 ), which may in part be related to a change in the diagnos-

tic criteria for functional dyspepsia used in the two trials ( 16 ). It is,

therefore, important for the Rome III criteria to be validated before

they are applied in trial design.

Th e results of our analysis suggest that PDS and EPS cannot

reliably be distinguished clinically. Th erefore, the value of divid-

ing patients into the subgroups of PDS and EPS is questionable

given the high degree of overlap between these two syndromes.

Furthermore, enrolling patients who have PDS alone or EPS alone

in treatment trials of functional dyspepsia may limit the applica-

bility of the results to the general functional dyspepsia popula-

tion in which PDS and EPS symptoms may frequently overlap.

Furthermore, approximately half of our primary care population

with PDS and / or EPS had concomitant GERD. In our study, the

presence of PDS did not predict a diagnosis of functional dys-

pepsia vs. GERD. Th e presence of EPS was weakly predictive of

functional dyspepsia vs. GERD, but with an odds ratio of < 3.

We also found that predominant heartburn and / or regurgitation

was not the primary determinant of whether a patient was clas-

sifi ed as having PDS or EPS, as many of the patients who met

criteria for both syndromes had heartburn or regurgitation as

their predominant symptom. Eliminating patients with predomi-

nant heartburn did not improve the discriminant ability of EPS

and PDS. New strategies are thus required for the classifi cation

of functional dyspepsia and its associated syndromes. Our data

also argue against the suggestion that individual drugs can be

of the three syndromes (PDS alone, EPS alone, and concomi-

tant PDS and EPS) was dependent on the duration of the most

bothersome upper gastrointestinal symptoms ( ≥ 6 months vs. < 6

months) in functional dyspepsia or GERD ( Table 8 ). If patients

with predominant symptoms of heartburn were eliminated from

the analysis, the results did not change signifi cantly. Th ere were 83

patients with GERD without predominant heartburn, of whom 45

(54.2 % ) met the criteria for both PDS and EPS, 19 (22.9 % ) for EPS

only and 19 (22.9 % ) for PDS only. Th ere were 98 patients with

functional dyspepsia who did not have predominant symptoms of

heartburn. Of these, 69 (70.4 % ) met the criteria for both EPS and

PDS, 19 (19.4 % ) met the criteria for EPS only and 10 (10.2 % ) met

the criteria for PDS only.

Logistic regression indicated that female gender, lower body

mass index, absence of hiatus hernia, and the presence of EPS

increased the probability of having functional dyspepsia compared

with GERD ( Table 9 ). Th e presence of PDS did not aff ect the prob-

ability of having functional dyspepsia or GERD ( Table 9 ).

DISCUSSION In an unselected primary care population, most patients with func-

tional dyspepsia who met Rome III criteria for PDS also met those

for EPS and vice versa . More than two-thirds of patients had six

Table 9 . Modeling the probability of having functional dyspepsia (vs. GERD) using logistic regression estimates of demographic and baseline variables

Variable OR (95 % CI) P value

Age 0.996 (0.978 – 1.014) 0.6726

Sex (female vs. male) 2.646 (1.599 – 4.379) 0.0002

BMI 0.899 (0.849 – 0.953) 0.0004

Hiatal hernia (present vs. absent) 0.412 (0.246 – 0.691) 0.0008

H. pylori (positive vs. negative) 1.344 (0.738 – 2.446) 0.3336

PDS (present vs. absent) 1.120 (0.657 – 1.911) 0.6769

EPS (present vs. absent) 2.910 (1.596 – 5.306) 0.0005

BMI, body mass index; CI, confi dence interval; EPS, epigastric pain syndrome; GERD, gastroesophageal refl ux disease; H. pylori , Helicobacter pylori ; OR, odds ratio; PDS, postprandial distress syndrome.

Table 8 . Distribution pattern of PDS and / or EPS in functional dyspepsia and GERD by duration of the predominant upper gastrointestinal symptoms

PDS alone n ( % ) EPS alone n ( % ) PDS + EPS n ( % ) P value

Functional dyspepsia with symptoms ≥ 6 months ( n =79) 10 (12.7) 19 (24.1) 50 (63.3) 0.2427

Functional dyspepsia with symptoms < 6 months ( n =51) 3 (5.9) 12 (23.5) 36 (70.6)

GERD with symptoms ≥ 6 months ( n =118) 25 (21.2) 33 (28) 60 (50.8) 0.7204

GERD with symptoms < 6 months ( n =41) 11 (26.8) 9 (22) 21 (51.2)

EPS, epigastric pain syndrome; GERD, gastroesophageal refl ux disease; PDS, postprandial distress syndrome. The Mantel – Haenszel test was used for proportions. Predominant symptoms defi ned as most and / or second most bothersome upper gastrointestinal symptoms.


774 S

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Vakil et al.

developed for the treatment of these syndromes. Any drug would

have to be eff ective in both PDS and EPS to be an eff ective agent

in functional dyspepsia.

Th e strengths of the Diamond study are its size, the unselected,

consecutive inclusion of the population of patients presenting

with upper gastrointestinal symptoms in primary care, the use

of endoscopy and the latest techniques for wireless pH-metry.

A major strength is that we used the best current methodology

to exclude GERD in the functional dyspepsia population, allow-

ing a careful assessment of the validity of syndrome subgroups

in patients with functional dyspepsia. We used a validated

patient-completed questionnaire to assess patient-reported

symptoms and a structured symptom list as part of the physician-

administered symptom assessment. Our entry criteria required

patients to have symptoms for at least 4 weeks, while the Rome

III criteria require symptoms to have been present for 6 months

( 1 ). However, our results show a similar distribution pattern

of PDS and / or EPS in patients with symptoms for 6 months or

less and those with symptoms for >6 months, both in GERD

and in functional dyspepsia. Our study has limitations inherent

to any post-hoc , retrospective data analysis in that the analyses

are exploratory.

In conclusion, the Rome III criteria for functional dyspepsia

did not distinguish reliably between PDS and EPS. Th e division of

functional dyspepsia into the subgroups of PDS and EPS may not

be eff ective in clinical trials or clinical practice. Further research is

required into dyspepsia subgroups before these criteria are applied

in clinical trials in dyspepsia.

ACKNOWLEDGMENTS Dr Anja Becher, from Oxford PharmaGenesis, provided writing

support funded by AstraZeneca R & D, M ö lndal, Sweden.

CONFLICT OF INTEREST Guarantor of the article : Nimish Vakil, MD, FACG.

Specifi c author contributions: Nimish Vakil: study concept and

design, acquisition of data, analysis and interpretation of data, writ-

ing of fi rst draft , critical revision of the manuscript for important

intellectual content. Katarina Halling: study concept and design,

analysis and interpretation of data, critical revision of the manu-

script for important intellectual content. Lis Ohlsson: study concept

and design, analysis and interpretation of data, critical revision of

the manuscript for important intellectual content, statistical analysis.

B ö rje Wernersson: study concept and design, analysis and inter-

pretation of data, critical revision of the manuscript for important

intellectual content.

Financial support: Th is study was funded by AstraZeneca R & D,

M ö lndal, Sweden.

Potential competing interests: Nimish Vakil has received

consultancy fees from AstraZeneca, Takeda Pharmaceutical,

XenoPort, Orexo and Ironwood Pharmaceuticals; has received

grant / research support from AstraZeneca and XenoPort; and has

ownership interest (e.g., stocks, stock options) in Orexo. Katarina

Halling, Lis Ohlsson, and B ö rje Wernersson are employed by

AstraZeneca R & D, M ö lndal, Sweden.

Study Highlights

WHAT IS CURRENT KNOWLEDGE 3 The Rome criteria are the most widely used criteria for

defi ning dyspepsia.

3 The Rome III criteria for functional dyspepsia recognize two distinct subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS).

3 Validation of the Rome III criteria dyspepsia subgroups of PDS and EPS is important before they are widely used in clinical and regulatory trials.

WHAT IS NEW HERE 3 Most patients with functional dyspepsia who meet Rome III

criteria for PDS also meet those for EPS and vice versa .

3 PDS is not predictive of functional dyspepsia vs. gastroesophageal refl ux disease (GERD).

3 EPS is a weak predictor of functional dyspepsia vs. GERD.

3 The value of dividing patients with functional dyspepsia into the subgroups of PDS and EPS is questionable given the high degree of overlap between these two groups.

3 Further research is required into dyspepsia subgroups before the Rome III criteria are applied in clinical trials in dyspepsia.

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