The basis for the decreased response to proton pump inhibitors in gastro-oesophageal reflux disease...

The basis for the decreased response to proton pump inhibitorsin gastro-oesophageal reflux disease patients without erosiveoesophagitis

J . D. GARDNER*, H. GALLO-TORRES� , S . SLOAN� , M. ROBINSON§ & P. B. MINER JR§

*Science for Organizations, Inc., Chatham, NJ, USA; �United States Food and Drug Administration, Rockville, MD, USA;

�Janssen Pharmaceutica Inc., Titusville, NJ, USA; §Oklahoma Foundation for Digestive Research, University of Oklahoma

Health Sciences Center, Oklahoma City, OK, USA

Accepted for publication 28 August 2003

SUMMARY

Background: The reason why heartburn in gastro-oeso-

phageal reflux disease subjects without oesophagitis is

less responsive to proton pump inhibitors than heartburn

in those with erosive oesophagitis is not known.

Methods: Gastric and oesophageal pH were determined

in 26 subjects with gastro-oesophageal reflux disease at

baseline and on days 1, 2 and 8 of treatment with

20 mg omeprazole or 20 mg rabeprazole in a random-

ized, two-way cross-over fashion. The presence or

absence of erosive oesophagitis at baseline was docu-

mented by upper gastrointestinal endoscopy.

Results: At a given value of the integrated gastric acidity

during treatment with a proton pump inhibitor, the

probability of pathological oesophageal reflux was

significantly higher in subjects with no oesophagitis

than in those with erosive oesophagitis. This occurred

because the post-prandial gastric acidity in subjects

with no oesophagitis showed a decreased response to

the antisecretory agent.

Conclusions: Compared with gastro-oesophageal reflux

disease subjects with erosive oesophagitis, those with no

oesophagitis are relatively refractory to the pharmaco-

dynamic effects of proton pump inhibitors on the post-

prandial integrated gastric acidity.

INTRODUCTION

In patients with gastro-oesophageal reflux disease

(GERD), the inhibition of gastric acid secretion with a

proton pump inhibitor is the mainstay of treatment of

oesophageal pathology and symptoms.1, 2 These drugs

decrease oesophageal as well as gastric acidity and

reduce the frequency and severity of heartburn.1–3 We

and others have reported that GERD subjects with

erosive oesophagitis have higher values of oesophageal

acid exposure than GERD subjects without erosive

oesophagitis.4, 5 On the other hand, heartburn in

subjects without erosive oesophagitis is less responsive

to proton pump inhibitors than heartburn in subjects

with erosive oesophagitis.6 In the present study, we

examined the relationship between oesophageal reflux

and gastric acidity in an attempt to establish a basis for

the reduced responsiveness to proton pump inhibitors in

GERD subjects without erosive oesophagitis — a group

that would be expected to have an increased respon-

siveness to proton pump inhibitors because of their

lower oesophageal acidity.4, 5

One reason for the lack of information regarding the

relationship between the effect of antisecretory treat-

ment on gastric acid secretion or gastric acidity and the

effect on other features in GERD has been the lack of

suitably precise analytical techniques. Previously, we

have described techniques using recordings of gastric

Correspondence to: Dr J. D. Gardner, Science for Organizations, Inc., 156

Terrace Drive, Chatham, NJ 07928, USA.

E-mail: [email protected]

Aliment Pharmacol Ther 2003; 18: 891–905. doi: 10.1046/j.1365-2036.2003.01777.x

� 2003 Blackwell Publishing Ltd 891

and oesophageal pH that can quantify acidity over

time.4, 7 A previous paper illustrated how these approa-

ches can be used to demonstrate the extent to which

gastric acidity has to be decreased to prevent

pathological oesophageal reflux in GERD subjects who

are being treated with a proton pump inhibitor.8

In the present study, we analysed data from 24-h

recordings of oesophageal and gastric pH during

treatment with a proton pump inhibitor to examine

possible relationships between gastric and oesophageal

acidity in GERD subjects stratified on the basis of

whether or not they had erosive oesophagitis. We found

that, at a given value of the integrated gastric acidity

during treatment with a proton pump inhibitor, GERD

subjects with no oesophagitis were significantly more

likely to experience pathological oesophageal reflux

than those with erosive oesophagitis.

Previously, we have found the following: (i) subjects

with GERD have increased meal-stimulated gastric acid

secretion; (ii) the post-prandial integrated gastric acidity

between 09.00 and 22.00 h is a good surrogate

measure for meal-stimulated gastric acid secretion;

and (iii) post-prandial, but not nocturnal, integrated

gastric acidity is significantly increased in GERD sub-

jects.9 In view of these findings, we examined whether

GERD subjects with no erosive oesophagitis were

refractory to the pharmacodynamic effects of proton

pump inhibitors on the post-prandial gastric acidity,

nocturnal gastric acidity or both. We found that the

reduced response to proton pump inhibitors in GERD

subjects with no oesophagitis occurred primarily with

regard to the post-prandial integrated gastric acidity.

METHODS

This study was approved by and conducted in compli-

ance with good clinical practices as supervised by the

Western Institutional Review Board, Olympia, WA,

USA. All subjects enrolled in the study gave written

informed consent.

The analyses reported in this paper are based on the

same data for gastric and oesophageal pH that have

been analysed previously.8, 9

Subjects

The subjects included 59 adults with a history of GERD

who had experienced heartburn at least four times per

week for at least 6 months (36 males, 23 females; age,

18–69 years). These subjects had no history of a serious

medical condition, no other clinically significant gas-

trointestinal illness, including peptic ulcer, no difficulty

swallowing thought to be due to a pathological process

other than simple oesophageal reflux, and no history of

a gastrointestinal haemorrhage, upper gastrointestinal

surgery, stricture or oesophageal dilation. Subjects had

not been treated with an investigational drug within

30 days prior to study entry. Subjects had not used

sucralfate, histamine H2-receptor antagonists, misopr-

ostol, proton pump inhibitors, pro-motility drugs or any

other medication that can alter gastric acid secretion or

gastrointestinal motility within 1 week of baseline pH

recording. Subjects had not used systemic corticoster-

oids, anticholinergics, antineoplastic agents, metoclopr-

amide, anticoagulants, tetracycline or cisapride within

1 month of baseline pH recording.

All subjects had a negative serology test for Helicobacter

pylori.

Study design

The study was conducted at the Oklahoma Foundation

for Digestive Research on the campus of the University

of Oklahoma Health Sciences Center.

Baseline 24-h gastric pH and oesophageal pH were

measured in 59 GERD subjects. Twenty-seven subjects

with oesophageal pH £ 4 for at least 10% of the 24-h

baseline recording period were then randomized to

receive eight consecutive daily doses of 20 mg omepraz-

ole or 20 mg rabeprazole in a cross-over fashion with a

14-day washout between the treatment periods. Of these

subjects, 26 underwent upper gastrointestinal endo-

scopy and oesophagitis was rated using the Hetzel–Dent

rating scale.10 Eight subjects had no erosive oesophagitis

(six grade 0; two grade 1) and 18 had erosive oesopha-

gitis (seven grade 2, seven grade 3 and four grade 4).

Gastric pH and oesophageal pH were measured for 24 h

on days 1, 2 and 8 with each treatment. The purpose of

the present analyses was to assess the effects of treatment

with a proton pump inhibitor, not to compare the results

obtained with omeprazole vs. rabeprazole.

Subjects fasted from approximately 22.00 h the even-

ing before until the beginning of pH recording the

following morning at 08.00 h. Standardized meals were

provided at breakfast, lunch, dinner and bedtime.

Smoking and the ingestion of food other than the test

meals were prohibited during the pH recording periods.

The caloric content and amounts of fat, carbohydrate

892 J. D. GARDNER et al.

� 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 18, 891–905

and protein in one portion of each meal were obtained

from the providers of the meals. Subjects were allowed to

ingest up to two portions of each meal, and the amounts

of each meal ingested were recorded. Subjects were

required to ingest the same amounts of food during all

24-h pH recording sessions. Meal 1 was ingested at

09.00 h and consisted of one McDonald’s sausage, egg,

cheese, biscuit with 30 g onions, 8 oz chocolate milk

and one peppermint patty. One portion contained 555

calories, with 31 g fat, 43 g carbohydrate and 27 g

protein. Meal 2 was ingested at 12.00 h and consisted of

one Wendy’s 8 oz chilli, one small frosty and 12 oz cola.

One portion contained 670 calories, with 15 g fat, 113 g

carbohydrate and 23 g protein. Meal 3 was ingested at

18.00 h and consisted of one Wendy’s hamburger with

cheese, one small French fries and 12 oz cola. One

portion contained 820 calories, with 33 g fat, 108 g

carbohydrate and 29 g protein. At bedtime (22.00 h)

subjects ingested a snack consisting of two Hostess

chocolate cupcakes and 8 oz whole milk.

Gastric pH and oesophageal pH values were collected

using an ambulatory, dual-channel pH recording system

(Medtronic Synectics) with antimony electrodes. One

electrode was placed in the stomach 10 cm below and the

second was placed in the oesophagus 5 cm above the

manometrically defined upper border of the lower oeso-

phageal sphincter. Electrodes were calibrated to pH 1 and

pH 7, and connected to a portable data storage unit

(Digitrapper, Medtronic Synectics). Recordings began at

08.00 h and continued for 24 h. Data were transferred

from the portable data storage unit and processed using

software designed for pH recordings (Polygram for

Windows, Version 2.04, Medtronic Synectics).

Analytical procedures

Polygram software takes the individual pH values that

are recorded every 4 or 8 s and fills in the same value

for the other seconds, resulting in one value for every

second of the recording period for each electrode. These

pH data were used for all calculations.

The integrated gastric and oesophageal acidity were

calculated for each hour of the recording period as

described previously.4, 7, 8

Statistical analyses

Statistical analyses were performed using GraphPad for

InStat version 3.01 for Windows. Curve fitting was

performed using GraphPad Prism version 4.00 for

Windows.

A step-by-step description of the analytical procedures

and the resulting graphs are given in Appendix A.

RESULTS

At baseline, the 24-h integrated oesophageal acidity in

subjects with erosive oesophagitis (median, 37.7

mmol.h/L; interquartile range, 17.5–74.5 mmol.h/L)

was not significantly different (P ¼ 0.080 by Mann–

Whitney test) from that in subjects with no oesophagitis

(18.5 mmol.h/L; 14.3–27.8 mmol.h/L). Typically,

GERD subjects with erosive oesophagitis have higher

oesophageal exposure than those without oesophagi-

tis;4, 5 however, the present study only included

subjects without oesophagitis who had oesophageal

pH £ 4 for at least 10% of the 24-h baseline recording

period. The value of the 24-h integrated gastric acidity

at baseline in GERD subjects with erosive oesophagitis

(1952 mmol.h/L; 1611–2204 mmol.h/L) was not sig-

nificantly different (P ¼ 0.177) from that in subjects

with no oesophagitis (1685 mmol.h/L; 1482–

1833 mmol.h/L).

Figure 1 compares subjects with erosive oesophagitis

with those with no oesophagitis with respect to the

distribution of values of the integrated oesophageal

acidity and integrated gastric acidity at baseline and

during treatment with a proton pump inhibitor. For

both oesophageal acidity and gastric acidity, the

distribution of values in GERD subjects with erosive

oesophagitis was not significantly different from that in

subjects with no oesophagitis (P ¼ 0.256 for oesopha-

geal acidity and P ¼ 0.522 for gastric acidity).

Furthermore, the area under the receiver operating

characteristic (ROC) curve11–14 was not significantly

different from 0.50 for both the oesophageal acidity

(area, 0.54; 95% confidence interval, [0.46, 0.64]) and

gastric acidity (0.52 [0.44, 0.62]).

It might be concluded that the lack of a significant

difference between GERD subjects with and without

erosive oesophagitis with respect to the oesophageal or

gastric acidity illustrated in Figure 1 indicates that these

two groups of subjects respond similarly to treatment

with a proton pump inhibitor. However, as the effect of

a proton pump inhibitor on the oesophageal acid

exposure results from the effect of the drug on the

gastric acidity, it is important to consider the oesopha-

geal acidity in relation to the accompanying value of the

PPI RESPONSIVENESS IN GERD WITHOUT OESOPHAGITIS 893


gastric acidity when comparing subjects with and

without erosive oesophagitis.

To compare the two groups of GERD subjects with

respect to the effect of the proton pump inhibitors on the

gastric acidity, we stratified all values of the integrated

gastric acidity for the accompanying value of the

integrated oesophageal acidity, using 8.1 mmol.h/L as

a cut-off point to define pathological oesophageal

acidity. From previous analyses of oesophageal pH

recordings from 26 healthy subjects and from the

baseline pH recordings from the 59 GERD subjects in the

present study, we found that a value of 8.1 mmol.h/L

for the 24-h integrated oesophageal acidity gives

maximal values of the sensitivity and specificity in

distinguishing between GERD subjects and healthy

subjects.8 The steps in this previous analysis are given

in Appendix A. Based on this analysis, we defined

pathological oesophageal reflux as a 24-h integrated

oesophageal acidity of greater than 8.1 mmol.h/L in the

present study. All subjects in the present study had

pathological oesophageal reflux at baseline, with a 24-h

integrated oesophageal acidity in the range 10.7–

120.4 mmol.h/L. This occurred because subjects were

selected on the basis of an oesophageal pH £ 4 for at

least 10% of the 24-h baseline recording period.

Figure 2 (left) illustrates that, in GERD subjects with

erosive oesophagitis, the percentage of values of the

integrated gastric acidity with pathological oesophageal

reflux (integrated oesophageal acidity above

8.1 mmol.h/L) is significantly higher than the percent-

age of values with no pathological oesophageal reflux

(integrated oesophageal acidity below 8.1 mmol.h/L)

across all values of the integrated gastric acidity

(P < 0.0001). The area under the ROC curve is 0.90

[0.85, 0.95] which, as pointed out previously,11–14

gives the probability that a randomly selected subject

with pathological oesophageal reflux will have a higher

value of the integrated gastric acidity than a randomly

selected subject with no pathological oesophageal

reflux.

Figure 2 (right) illustrates that, in GERD subjects with

no oesophagitis, the percentage of values of the


reflux is also significantly higher than the percentage of

values with no pathological oesophageal reflux at all

values of the integrated gastric acidity (P < 0.0001).

When Figure 2 (left) is compared with Figure 2 (right),

however, there is a greater separation of the curves for

GERD subjects with erosive oesophagitis than for

subjects with no oesophagitis.

The area under the ROC curve in Figure 2 (right)

(0.68 [0.53, 0.82]) is significantly lower than the area

under the ROC curve in Figure 2 (left) (P ¼ 0.0046).

These differences between the areas under the ROC

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Figure 1. Values of the 24-h integrated oesophageal acidity (left panel) and integrated gastric acidity (right panel) from gastro-

oesophageal reflux disease (GERD) subjects stratified for the presence or absence of erosive oesophagitis. Both panels plot the percentage of

subjects with values of the integrated acidity above the value indicated on the X-axis. Results are from 24-h measurements in 18 subjects

with erosive oesophagitis and eight subjects with no erosive oesophagitis at baseline and during treatment with each of two different

proton pump inhibitors for 1, 2 and 8 days.



curves indicate that the integrated gastric acidity

discriminates better between pathological and normal

oesophageal reflux in subjects with erosive oesophagitis

than in subjects with no oesophagitis. This difference, in

turn, reflects the difference between GERD subjects with

and without erosive oesophagitis in terms of their

response to proton pump inhibitors.

Previously, we described a method to determine the

probability that a subject with a particular value of the

integrated gastric acidity will have no pathological

oesophageal reflux.8 With this method, we calculated

the probability of no pathological reflux by dividing the

number of records with an integrated oesophageal

acidity below 8.1 mmol.h/L by the total number of

records at each value of the integrated gastric acidity.

The details of this method are given in Appendix A. We

used this same approach in the present study to

compare the results from GERD subjects with and

without erosive oesophagitis. Figure 3 illustrates the

probability of no pathological reflux as a function of the

integrated gastric acidity for GERD subjects with and

without erosive oesophagitis.

Both curves in Figure 3 have the same configuration

in that, at relatively low values of the integrated gastric

acidity, there is an initial plateau at 100% on the X-axis,

i.e. where the probability of no pathological reflux is

100%. This plateau extends to values of the integrated

gastric acidity of 301 mmol.h/L in subjects with erosive

oesophagitis and 125 mmol.h/L in subjects with no

erosive oesophagitis. At higher values of the integrated

gastric acidity, the curve decreases in a curvilinear

fashion to a second plateau at 60–65%. This second

plateau reflects the overall prevalence of records with no

pathological oesophageal reflux in the two groups of

subjects. That is, 64% of the pH recordings from subjects

with erosive oesophagitis have values of the integrated

oesophageal acidity below 8.1 mmol.h/L and 61% of

the recordings from subjects with no oesophagitis have

values of the integrated oesophageal acidity below this

same value. At values between the two plateaux, the

curve for the subjects with no oesophagitis is below that

for the subjects with erosive oesophagitis.

The results in Figure 3 indicate that, during treatment

with a proton pump inhibitor, the prevention of patho-

logical oesophageal reflux requires a greater decrease in

the integrated gastric acidity in subjects without

oesophagitis than in subjects with erosive oesophagitis.

This interpretation is supported by the finding that the

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Figure 2. Values of the 24-h integrated gastric acidity stratified for 24-h integrated oesophageal acidity above or below 8.1 mmol.h/L in

gastro-oesophageal reflux disease (GERD) subjects with erosive oesophagitis (left panel) or without erosive oesophagitis (right panel). Both

panels plot the percentage of records with values of the integrated gastric acidity above the value indicated on the X-axis. The area under

the receiver operating characteristic curve [95% confidence interval] for the data in the left panel is 0.899 [0.846, 0.952] and for the data

in the right panel is 0.675 [0.530, 0.821]. Results are from 24-h measurements in 18 subjects with erosive oesophagitis and eight

subjects with no erosive oesophagitis at baseline and during treatment with each of two different proton pump inhibitors for 1, 2 and

8 days.



initial plateau of the curve for subjects with erosive

oesophagitis extends to a higher value (301 mmol.h/L)

than that for subjects with no oesophagitis (125 mmol.h/

L). Figure 3 also illustrates that the overall prevalence of

no pathological oesophageal reflux is the same in the two

groups, and excludes a difference in overall prevalence as

an explanation for the different sensitivity to proton pump

inhibitors between the two groups.

The data in Figure 3 can be fitted by an equation with

an initial plateau and then an exponential decrease to a

second plateau with increasing integrated gastric acid-

ity. The parameters for this equation are given in

Table 1. The high values of R2 indicate that both curves

give good fits of the data illustrated in Figure 3. The

curve for GERD subjects without erosive oesophagitis is

significantly lower than the corresponding curve for

subjects with erosive oesophagitis (P < 0.0001).

Next, we examined the pharmacodynamic effects of

proton pump inhibitors on the post-prandial gastric

acidity and nocturnal gastric acidity and their associ-

ation with pathological oesophageal reflux. At baseline,

the median post-prandial integrated gastric acidity in

GERD subjects with erosive oesophagitis (552 mmol.h/

L) was not significantly different (P ¼ 0.177) from that

in subjects with no oesophagitis (406 mmol.h/L).

Similarly, at baseline, the median nocturnal integrated

gastric acidity in GERD subjects with erosive oesopha-

gitis (1321 mmol.h/L) was not significantly different

(P ¼ 0.495) from that in subjects with no oesophagitis

(1287 mmol.h/L). Furthermore, the distributions of the

values of the post-prandial and nocturnal gastric acidity

at baseline and during treatment with a proton pump

inhibitor in subjects with erosive oesophagitis were not

significantly different from the corresponding distribu-

tions in subjects with no oesophagitis (P ¼ 0.994 for

post-prandial acidity and P ¼ 0.306 for nocturnal

acidity). The area under the ROC curve was not

significantly different from 0.50 for both post-prandial

acidity (area, 0.50; 95% confidence interval, [0.41,

0.59]) and nocturnal acidity (0.55 [0.46, 0.64]).

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Figure 3. Probability of no pathological oesophageal reflux with

different values of the integrated gastric acidity in subjects with or

without erosive oesophagitis. Each value is the percentage of

records with no pathological reflux at the indicated value of the

integrated gastric acidity. Results are from 24-h measurements in

18 subjects with erosive oesophagitis and eight subjects with no

erosive oesophagitis at baseline and during treatment with each of

two different proton pump inhibitors for 1, 2 and 8 days. Notice

that the vertical axis is truncated at 40. The full lines are the best-

fit lines using the equation and parameters given in Table 1.

Table 1. Parameters for the curve descri-

bing the probability of no pathological

oesophageal reflux as a function of the

integrated gastric acidity in gastro-oeso-

phageal reflux disease (GERD) subjects

treated with a proton pump inhibitor

Parameter Erosive oesophagitis No erosive oesophagitis

Initial plateau (%) 100 [99.6, 100.4] 103 [98, 109]

X0 (mmol.h/L) 235 [206, 264] 0

Final plateau (%) 30 [20, 41] 66 [64, 68]

Exponential coefficient

(1/mmol.h/L)

3.1 · 10)4 [2.5, 3.8 · 10)4] 3.2 · 10)3 [2.3, 4.0 · 10)3]

R2 0.992 0.818

Parameter values are from a least-squares fit of the data illustrated in Figure 3 from 18 GERD

subjects with erosive oesophagitis and eight subjects with no erosive oesophagitis at baseline

and during days 1, 2 and 8 of treatment with each of two proton pump inhibitors. X0 is the

value on the X-axis that represents the upper boundary of the initial plateau. The values in

square brackets are the 95% confidence intervals. The equation fitted was: when X < X0,

Y ¼ initial plateau; when X > X0, Y ¼ final plateau + (span · e– a(X ) X0)), where

span ¼ initial plateau ) final plateau.



Figure 4 (left) illustrates that, in all GERD subjects

considered together during treatment with a proton

pump inhibitor, the percentage of values of the post-

prandial integrated gastric acidity with pathological

oesophageal reflux is significantly higher than the

percentage of values with no pathological oesophageal

reflux (P < 0.0001). The area under the ROC curve for

these data is 0.86 and indicates that the post-prandial

gastric acidity distinguishes between pathological and

non-pathological oesophageal reflux as well as or better

than the 24-h integrated gastric acidity.

Figure 4 (middle) illustrates that, in GERD subjects

with erosive oesophagitis, the percentage of values of the

post-prandial gastric acidity with pathological oesopha-

geal reflux is significantly higher than the percentage of

values with no pathological oesophageal reflux

(P < 0.0001). The area under the ROC curve is 0.89

[0.83, 0.95]. Figure 4 (right) illustrates that, in GERD

subjects with no erosive oesophagitis, the percentage of

values of the post-prandial gastric acidity with patholo-

gical oesophageal reflux is not significantly higher than

the percentage of values with no pathological oesopha-

geal reflux (P ¼ 0.156). The area under the ROC curve

for the data in Figure 4 (right) is 0.61 [0.47, 0.76] — a

value that is not significantly different from 0.50 and

that is significantly lower than the area under the ROC

curve in Figure 4 (middle) (P ¼ 0.00062). This differ-

ence between the areas under the ROC curves indicates

that the post-prandial gastric acidity discriminates

between pathological and normal oesophageal reflux

in subjects with erosive oesophagitis, but not in subjects

with no oesophagitis. This difference, in turn, reflects the

difference between GERD subjects with and without

erosive oesophagitis in their response to proton pump

inhibitors. In other words, in subjects with erosive

oesophagitis treated with a proton pump inhibitor, on

average 89% of records with pathological oesophageal

reflux will have a higher value of the post-prandial

gastric acidity than records with normal oesophageal

reflux. In contrast, in subjects with no oesophagitis

treated with a proton pump inhibitor, the likelihood that

records with pathological oesophageal reflux will have a

higher value of the post-prandial gastric acidity than

records with normal oesophageal reflux is not signifi-

cantly different from chance alone.

Figure 5 (left) illustrates that, in all GERD subjects

considered together during treatment with a proton

pump inhibitor, the percentage of values of the nocturnal


reflux is significantly higher than the percentage of

values with no pathological oesophageal reflux

(P < 0.0001). Figure 5 (middle) illustrates that, in GERD

subjects with erosive oesophagitis, the percentage of

values of the nocturnal gastric acidity with pathological

oesophageal reflux is significantly higher than the

percentage of values with no pathological oesophageal

reflux (P < 0.0001). The area under the ROC curve for

these data is 0.84 [0.76, 0.92]. Figure 5 (right) illustrates

that, in GERD subjects with no erosive oesophagitis, the

percentage of values of the nocturnal gastric acidity with

pathological oesophageal reflux is significantly higher

than the percentage of values with no pathological

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xis

(%)

Above 8.1 Below 8.1

0

10

20

30

40

50

60

70

80

90

100

0 200 400 600 800 1000 1200

Above 8.1 Below 8.1

Rec

ord

ing

s w

ith

Inte

gra

ted

Gas

tric

Aci

dit

yA

bo

ve V

alu

e G

iven

on

X-a

xis

(%)

Post-prandial Integrated Gastric Acidity(mmol.h/L)

Figure 4. Values of the post-prandial integrated gastric acidity stratified for 24-h integrated oesophageal acidity above or below

8.1 mmol.h/L. Results are from all subjects (left panel) (n ¼ 26), subjects with erosive oesophagitis (middle panel) (n ¼ 18) and subjects

with no erosive oesophagitis (right panel) (n ¼ 8). Each panel plots the percentage of records with values of the integrated gastric acidity

above the value indicated on the X-axis. The area under the receiver operating characteristic curve [95% confidence interval] for results

in the left panel is 0.855 [0.779, 0.894], in the centre panel is 0.892 [0.833, 0.952] and in the right panel is 0.614 [0.466, 0.762].

Results are from measurements at baseline and during treatment with each of two different proton pump inhibitors for 1, 2 and 8 days.



oesophageal reflux (P < 0.0001). The area under the

ROC curve for these data is 0.69 [0.55, 0.84].

Thus, in subjects with erosive oesophagitis treated

with a proton pump inhibitor, normal oesophageal

reflux is significantly more likely than pathological

oesophageal reflux to be accompanied by lower values

of both the post-prandial (Figure 4) and nocturnal

(Figure 5) gastric acidity. In contrast, in subjects with

no oesophagitis, normal oesophageal reflux is signifi-

cantly more likely to be accompanied by lower values of

nocturnal (Figure 5), but not post-prandial (Figure 4),

gastric acidity.

Figure 6 illustrates the probability of no patholo-

gical reflux as a function of the post-prandial and

0

10

20

30

40

50

60

70

80

90

100

0 300 600 900 1200 1500 1800 2100

Nocturnal Integrated Gastric Acidity (mmol.h/L)

Rec

ord

ings

with

Inte

gra

ted

Gas

tric

Aci

dity

Ab

ove

Val

ue

Giv

eno

n X

-axi

s (%

)

Above 8.1 Below 8.1

0

10

20

30

40

50

60

70

80

90

100

0 300 600 900 1200 1500 1800 2100


Rec

ord

ing

sw

ith

Inte

grat

edG

astr

icA

cidi

tyA

bove

Val

ueG

iven

onX

-axi

s (%

)

Above 8.1 Below 8.1

0

10

20

30

40

50

60

70

80

90

100

0 300 600 900 1200 1500 1800 2100


Rec

ord

ing

sw

ith

Inte

gra

ted

Gas

tric

Aci

dity

Ab

ove

Val

ueG

iven

onX

-axi

s (%

)

Above 8.1 Below 8.1

Figure 5. Values of the nocturnal integrated gastric acidity stratified for 24-h integrated oesophageal acidity above or below 8.1 mmol.h/L.

Results are from all subjects (left panel) (n ¼ 26), subjects with erosive oesophagitis (middle panel) (n ¼ 18) and subjects with no erosive

oesophagitis (right panel) (n ¼ 8). Each panel plots the percentage of records with values of the integrated gastric acidity above the value

indicated on the X-axis. The area under the receiver operating characteristic curve [95% confidence interval] for results in the left panel is

0.836 [0.775, 0.896], in the centre panel is 0.837 [0.759, 0.915] and in the right panel is 0.691 [0.547, 0.835]. Results are from

measurements at baseline and during treatment with each of two different proton pump inhibitors for 1, 2 and 8 days.

Post-prandial Gastric Acidity Nocturnal Gastric Acidity

40

50

60

70

80

90

100

0 200 400 600 800 1000 1200

Integrated Post-prandial Gastric Acidity(mmol.h/L)

Pro

bab

ility

of

No

Pat

ho

log

ical

Oes

op

hag

eal

Ref

lux


40

50

60

70

80

90

100

0 300 600 900 1200 1500 1800 2100

Integrated Nocturnal Gastric Acidity (mmol.h/L)

Pro

bab

ility

of

No

Pat

ho

log

ical

Oes

op

hag

eal

Ref

lux


Figure 6. Probability of no pathological oesophageal reflux with different values of the integrated gastric acidity in subjects with or

without erosive oesophagitis. Each value is the percentage of records with no pathological reflux at the indicated value of the integrated

gastric acidity. Results are from 24-h measurements in 18 subjects with erosive oesophagitis and eight subjects with no erosive

oesophagitis at baseline and during treatment with each of two different proton pump inhibitors for 1, 2 and 8 days. Notice that the

vertical axis is truncated at 40. The full lines are the best-fit lines using the equation and parameters given in Table 2.



nocturnal gastric acidity for GERD subjects with and

without erosive oesophagitis. Both curves for the post-

prandial gastric acidity have the same configuration

in that the curve decreases in a curvilinear fashion

from 100% at no post-prandial gastric acidity to a

second plateau at 60–65% at the highest values of

post-prandial gastric acidity. As pointed out earlier in

this paper, this second plateau reflects the overall

prevalence of records with no pathological oesopha-

geal reflux in the two groups of subjects. At values

between the two plateaux, the curve for subjects with

no oesophagitis is significantly below that for subjects

with erosive oesophagitis, indicating that, during

treatment with a proton pump inhibitor, the preven-

tion of pathological oesophageal reflux requires a

greater decrease in the post-prandial integrated gastric

acidity in subjects without erosive oesophagitis than

in those with erosive oesophagitis.

In Figure 6 (right), the curves for the nocturnal gastric

acidity are closer together than the corresponding

curves for the post-prandial gastric acidity in Figure 6

(left). Like the curves in Figure 6 (left), however, both

curves decrease in a curvilinear fashion from 100%

with no nocturnal gastric acidity to a second plateau at

60–65% with the highest values of nocturnal gastric

acidity. Figure 6 also illustrates that the overall preval-

ence of no pathological oesophageal reflux is the same

in the two groups of GERD subjects, and excludes a

difference in the overall prevalence as an explanation

for the different sensitivity to proton pump inhibitors

between the two groups.

The data in Figure 6 can be fitted by an equation with

an exponential decrease to a plateau with increasing

post-prandial or nocturnal integrated gastric acidity.

The parameters for this equation are given in Table 2.

The high values of R2 indicate that both curves give

good fits of the data illustrated in Figure 6. For both the

post-prandial and nocturnal gastric acidity, the curve

for GERD subjects without erosive oesophagitis is

significantly lower than the corresponding curve for

subjects with erosive oesophagitis (P < 0.0001). This

difference with both post-prandial and nocturnal gastric

acidity is indicated by the significantly lower exponen-

tial coefficients for the data from subjects with erosive

oesophagitis compared with those for the data from

subjects with no oesophagitis. The curves in Figure 6

(left) for the post-prandial gastric acidity are further

apart than the curves in Figure 6 (right) for the

nocturnal gastric acidity. Similarly, the exponential

coefficients in Table 2 differ by a factor of 10 for the

post-prandial gastric acidity, but only by a factor of

2.4 for the nocturnal gastric acidity.

Figure 4 (right) displays the results for subjects with

no erosive oesophagitis and shows that, in terms of the

distribution of values of the post-prandial gastric acidity,

there is no significant difference between records with

and without pathological oesophageal reflux; the area

under the ROC curve for these data does not differ

significantly from 0.50 (P ¼ 0.154). On the other hand,

Figure 6 (left) and Table 2 illustrate that, in subjects

with no oesophagitis, there is a highly significant

relationship between the probability of no pathological

oesophageal reflux and the value of the post-prandial

gastric acidity calculated from the same data as

illustrated in Figure 4 (right). This apparent discrep-

ancy results from the fact that the analyses in Figure 4

(right) are independent of the prevalence of pathological

oesophageal reflux, whereas those in Figure 6 (left)

Table 2. Parameters for the curve descri-

bing the probability of no pathological

oesophageal reflux as a function of the post-

prandial or nocturnal integrated gastric

acidity in gastro-oesophageal reflux disease

(GERD) subjects treated with a proton

pump inhibitor

Exponential coefficient

[(1/(mmol.h/L)) · 10)3] R2

Post-prandial integrated gastric acidity

Erosive oesophagitis 1.91 (0.038) 0.967

No erosive oesophagitis 20.17 (2.22) 0.790

Nocturnal integrated gastric acidity

Erosive oesophagitis 1.01 (0.025) 0.883

No erosive oesophagitis 2.44 (0.184) 0.596

Parameter values are from a least-squares fit of the data illustrated in Figure 6 from 18 GERD

subjects with erosive oesophagitis and eight subjects with no erosive oesophagitis at baseline

and during days 1, 2 and 8 of treatment with each of two proton pump inhibitors. Values in

parentheses are the standard errors. The equation fitted was Y ¼ plateau + (span · e– aX),

where span ¼ 100 ) plateau. All results for the post-prandial integrated gastric acidity were

fitted together and all values for the nocturnal integrated gastric acidity were fitted together.

All data were fitted by constraining the value of the plateau to 62.



depend critically on the prevalence of oesophageal

reflux at all values of the post-prandial gastric acidity.

We have discussed this phenomenon previously,8, 15

and it is described in detail elsewhere.16, 17

If we examine the values of the post-prandial gastric

acidity below 200 mmol.h/L in Figure 4 (right), it is

clear that values with no pathological oesophageal

reflux are consistently below those with pathological

reflux (even though the overall distributions are not

significantly different). These differences correspond to

and account for the increasing probability of no

pathological oesophageal reflux at values of the post-

prandial gastric acidity below 200 mmol.h/L in Figure 6

(left).

DISCUSSION

The main purpose of the present analyses was to

compare the relationship between gastric acidity and

oesophageal acidity during treatment with a proton

pump inhibitor in GERD subjects with and without

erosive oesophagitis. In previous studies, we have found

that GERD subjects exhibit increased meal-stimulated

gastric acid secretion as well as increased post-prandial

gastric acidity.9 We considered the possibility that,

during treatment with a proton pump inhibitor, GERD

subjects with no erosive oesophagitis might have

increased gastric acidity and an accompanying increase

in oesophageal acidity that could account for their

reduced symptomatic response to treatment. We exam-

ined the distribution of values of oesophageal and

gastric acidity in GERD subjects with and without

erosive oesophagitis during treatment with a proton

pump inhibitor, and found no difference between the

groups for either oesophageal or gastric acidity. These

results indicate that the reduced symptomatic response

to proton pump inhibitor treatment in subjects with no

oesophagitis6 cannot be attributed to increased oeso-

phageal or gastric acidity per se.

Previously, we have found that, at a given value of the

integrated gastric acidity during treatment with a

proton pump inhibitor, the proportion of GERD subjects

with pathological oesophageal reflux is significantly

higher than the proportion of GERD subjects without

pathological oesophageal reflux.8 In addition, there is a

precise quantitative relationship between the integrated

gastric acidity and the probability of pathological

oesophageal reflux. In the present study, we found that

these previous findings also applied to GERD subjects

stratified on the basis of whether or not they had erosive

oesophagitis. That is, at a given value of the integrated

gastric acidity during treatment with a proton pump

inhibitor, the percentage of values of the integrated

gastric acidity with pathological oesophageal reflux was

significantly higher than the percentage of values with

no pathological oesophageal reflux in both groups of

GERD subjects. We also found that the probability of

pathological oesophageal reflux could be predicted with

high precision from the value of the integrated gastric

acidity using an equation that gave the probability of

pathological oesophageal reflux as an exponential

function of the integrated gastric acidity.

However, the magnitude of the quantitative relation-

ship between the integrated gastric acidity and the

prevalence of pathological oesophageal reflux differed

significantly between the two groups of GERD subjects.

First, the area under the ROC curve for pathological vs.

no pathological oesophageal acidity for subjects with

erosive oesophagitis was significantly higher than that

for subjects with no oesophagitis. These results indicate

that, in subjects with erosive oesophagitis, the probab-

ility that a randomly selected subject with pathological

oesophageal reflux will have a higher value of the

integrated gastric acidity than a randomly selected

subject with no pathological oesophageal reflux is

significantly higher than the probability in subjects

with no oesophagitis. Second, we found that, at a given

value of the integrated gastric acidity during treatment

with a proton pump inhibitor, GERD subjects with no

oesophagitis were significantly more likely than subjects

with erosive oesophagitis to experience pathological

oesophageal reflux.

As mentioned previously, compared with subjects with

erosive oesophagitis, the response to proton pump

inhibitors in GERD subjects without erosive oesophagitis

is paradoxical in that these subjects generally have

lower oesophageal acid exposure,4, 5 but have less relief

of heartburn during treatment with a proton pump

inhibitor.6 The present findings resolve this paradox by

showing that GERD subjects with no oesophagitis are

relatively refractory to the pharmacodynamic effects of

proton pump inhibitors on gastric and oesophageal

acidity. Previous analyses of oesophageal and gastric

acidity, as well as the effects of proton pump inhibitors

on these measures, have lacked suitable techniques for

quantifying acidity. Traditionally, the time at pH £ 4

has been used to assess oesophageal as well as gastric

acidity.1, 18, 19 In the present study, we did not use



these measures because they are less sensitive than the

integrated acidity for evaluating gastric and oesopha-

geal pH recordings and for assessing the relationship

between the integrated gastric acidity and the probab-

ility of no pathological oesophageal reflux during

treatment with a proton pump inhibitor.4, 7, 8

The present results, however, may apply only to GERD

subjects treated with a proton pump inhibitor. Studies

in similar subjects treated with a histamine H2-receptor

antagonist might give different results, because these

agents have a different duration of action on gastric acid

secretion, different effects on gastric pH during fasting

and inhibit fasting gastric acid secretion to a greater

extent than meal-stimulated secretion.20–22

It is important to recognize that the two groups of GERD

subjects were not selected on the basis of matching

features, such as age, gender, weight, previous medica-

tions, etc., and contained unequal numbers of subjects

(18 vs. 8). These characteristics of the study may have

introduced bias that influenced our results. In addition, it

is important to recognize that the present findings apply

only to the subset of GERD subjects with no oesophagitis

who have pathological oesophageal acid exposure,

because subjects selected for the present study had

oesophageal pH £ 4 for at least 10% of the 24-h

baseline recording period. (Approximately 50% of GERD

subjects with no oesophagitis have pathological oeso-

phageal acid exposure.1) The selection of subjects with

pathological oesophageal acid exposure resulted in two

groups of GERD subjects that were similar in terms of

gastric acidity, oesophageal acidity and the overall

prevalence of pathological oesophageal reflux at baseline

and during treatment with a proton pump inhibitor.

These similarities made it possible to analyse the rela-

tionship between pathological oesophageal reflux and the

integrated gastric acidity during treatment with a proton

pump inhibitor without having to adjust for between-

group differences in gastric or oesophageal acidity or the

overall prevalence of pathological oesophageal reflux.

We found that the post-prandial integrated gastric

acidity and nocturnal integrated gastric acidity were at

least as effective as the 24-h integrated gastric acidity in

distinguishing between pathological and non-patholo-

gical oesophageal reflux. This finding was anticipated,

because proton pump inhibitors act on gastric acid

secretion for at least 24-h and are highly effective in

reducing post-prandial as well as nocturnal gastric

acidity.1, 2 The distribution of the values of the post-

prandial and nocturnal gastric acidity in GERD subjects

with erosive oesophagitis did not differ from that in

subjects with no oesophagitis. These results indicate

that the reduced symptomatic response to proton pump

inhibitor treatment in subjects with no erosive oesopha-

gitis6 cannot be attributed to a difference in post-

prandial or nocturnal gastric acidity per se.

Previously, we have found that the meal-stimulated

gastric acid secretion and post-prandial integrated

gastric acidity from 09.00 to 22.00 h are significantly

higher in GERD subjects than in control subjects.9 The

integrated gastric acidity during the entire 24-h record-

ing period and during the nocturnal period from 22.00

to 09.00 h does not differ significantly between GERD

subjects and control subjects. As pathological oesopha-

geal reflux during the post-prandial period is common in

GERD,1 and as we have found that, in GERD subjects,

gastric acidity and secretion are significantly increased

during the post-prandial period,9 it seems likely that this

increased gastric acidity is an important aetiological

factor in GERD. Moreover, the oesophageal acid con-

centration during oesophageal reflux episodes correlates

with the post-prandial gastric acidity in GERD subjects,

but not in control subjects.9

The present analyses indicate that the reduced respon-

siveness to proton pump inhibitors in subjects with no

oesophagitis occurs primarily with regard to the post-

prandial gastric acidity. In these subjects, reducing the

post-prandial gastric acidity with a proton pump

inhibitor is significantly less effective in reducing the

likelihood of pathological oesophageal reflux than in

subjects with erosive oesophagitis. Although a similar

phenomenon occurs with the nocturnal gastric acidity,

the difference in the probability of pathological oeso-

phageal reflux between subjects with and without

erosive oesophagitis is clearly less than that found with

the post-prandial gastric acidity. The finding that most

subjects with GERD experience heartburn after a meal,1

and that the post-prandial gastric acidity in subjects

with no erosive oesophagitis is less responsive to proton

pump inhibitors, is consistent with and can account for

the reduced symptomatic response to proton pump

inhibitors in this group of GERD subjects.

The effect of gastric antisecretory agents on gastric

acid secretion can be partitioned into the effect on

volume secretion and the effect on the acid concentra-

tion in the secreted fluid. The finding that GERD subjects

with no erosive oesophagitis are relatively resistant to

the effects of proton pump inhibitors on the pathological

oesophageal reflux, and that this resistance occurs



primarily during meal-stimulated gastric acid secretion,

raises the possibility that proton pump inhibitors have a

smaller effect on the post-prandial volume secretion in

subjects with no oesophagitis than in subjects with

erosive oesophagitis. The resulting increased volume

could predispose these subjects to post-prandial oeso-

phageal reflux. A smaller effect of proton pump

inhibitors on the post-prandial volume alone should

also lead to increased post-prandial gastric acidity

resulting from greater meal-stimulated gastric acid

secretion (higher volume secreted with the same acid

concentration). In the present analyses, however, we

found that the post-prandial integrated gastric acidity

in subjects with no oesophagitis was not significantly

different from that in subjects with erosive oesopha-

gitis under basal conditions or during treatment with

a proton pump inhibitor. It may be that, although the

post-prandial integrated gastric acidity is a good

surrogate for meal-stimulated gastric acid secretion

under basal conditions,9 this may not be the case

during treatment with a proton pump inhibitor. As

pointed out previously,9 during treatment with a

proton pump inhibitor, it is often not possible to

measure meal-stimulated gastric acid secretion by

in vivo autotitration.23 With proton pump inhibitor

treatment, the post-prandial gastric pH frequently fails

to return to below pH 2, making it impossible to

calculate secretion.

Another possible explanation for our findings is that,

during proton pump inhibitor treatment of GERD

subjects with no oesophagitis, there is no absolute

increase in post-prandial gastric volume secretion, but

only an increase in volume secretion relative to the acid

concentration in the secreted fluid. Such a situation

could result in pathological oesophageal reflux in

subjects with no oesophagitis, but not in subjects with

erosive oesophagitis, even though both groups have the

same value of the post-prandial integrated gastric

acidity.

An anonymous reviewer pointed out that it is

important to consider the possible effect of transient

lower oesophageal sphincter relaxations, which are

thought to be the main mechanism underlying post-

prandial gastro-oesophageal reflux,24–30 on the differ-

ences between subjects with and without erosive

oesophagitis observed in the present study. The reviewer

pointed out that transient lower oesophageal sphincter

relaxations are probably triggered by accommodation

differences between GERD patients and normal subjects,

resulting in a vagal reflex that causes such relaxations

without a swallow stimulus from above. Thus, GERD

subjects without oesophagitis may have more post-

prandial transient lower oesophageal sphincter relaxa-

tions than those with erosive oesophagitis due to a

larger post-prandial gastric fluid secretion. Subjects with

erosive oesophagitis may have more fundamental lower

oesophageal sphincter dysfunction that causes excessive

oesophageal acid exposure at times other than the post-

prandial period and results in erosive injury to the

oesophageal mucosa.

The data for the probability of no pathological

oesophageal reflux as a function of the 24-h integrated

gastric acidity were fitted with an equation that

included an initial plateau when the probability of

no pathological oesophageal reflux was 100%, fol-

lowed by an exponential decrease in the probability to

a second plateau that reflected the overall prevalence

of no pathological oesophageal reflux (62%). On the

other hand, with both the post-prandial and nocturnal

gastric acidity, the data for the probability of patho-

logical oesophageal reflux were fitted by an equation

that did not include an initial plateau at a probability

of 100%. As the data for the prevalence of patholo-

gical oesophageal reflux were the same in the two

analyses, the different equations reflect different distri-

butions of the values for the probability of pathological

oesophageal reflux with respect to the different meas-

ures of integrated gastric acidity. In the analyses of the

post-prandial and nocturnal gastric acidity, although

there were a number of lower values of gastric acidity

where the probability of no pathological oesophageal

reflux was 100%, these values did not have a

sufficiently large impact on the fit of the entire data

set to require an initial plateau in the equation. It is

important to emphasize, however, that the equations

used to relate the gastric acidity to the probability of

no pathological oesophageal reflux have no patho-

physiological significance that we are aware of. They

simply give the mathematical relationships that best

describe the data.

ACKNOWLEDGEMENTS

We thank the anonymous reviewer who made major

contributions to this paper by suggesting the current

layout of the figures and tables and by pointing out the

potential role of transient lower oesophageal sphincter

relaxations in our findings.



This work was supported by grants from the Janssen

Pharmaceutica Research Foundation to the Oklahoma

Foundation for Digestive Research and to Science for

Organizations, Inc.

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APPENDIX A

This appendix describes the analytical methods used

in the present paper. The data used are from a

previous publication in which we determined the

value of the 24-h integrated oesophageal acidity that

gave optimal sensitivity and specificity for distinguish-

ing between GERD subjects and normal subjects (see

Table A1).8

Description of values in Table A1

(a) Values of the integrated oesophageal acidity from

GERD subjects were ordered from lowest to highest.

The values are recorded in column A and the ranks

(1–57) are recorded in column B.

(b) Values of the integrated oesophageal acidity from

normal subjects were ordered from lowest to

highest. The values are recorded in column A

immediately following those from GERD subjects

and the ranks (1–26) are recorded in column B.

(c) All values of the integrated oesophageal acidity in

column A were ordered from lowest to highest

whilst maintaining the rank values recorded in

columns B and C.

(d) Each value in columns B and C was carried down

the column to the next recorded value. Blanks

before the first recorded value in column B or C

were assigned a value of zero.

(e) The values in column B now indicate the number of

GERD subjects with values of the integrated oeso-

phageal acidity equal to or less than the corres-

ponding value in column A.

(f) The values in column C now indicate the number of

normal subjects with values of the integrated

oesophageal acidity equal to or less than the

corresponding value in column A.

(g) Each value in column B was divided by the total

number of GERD subjects (57), subtracted from 1,

multiplied by 100 and the result recorded in the

corresponding space in column D. The values in

column D give the percentage of GERD subjects with

Table A1. Integrated oesophageal acidity

providing optimal sensitivity and specificity

for distinguishing between subjects with

gastro-oesophageal reflux disease (GERD)

and normal subjects

A

Integrated oesophageal

acidity (mmol.h/L)

B

Rank

GERD

C

Rank

normal

D

Per cent

GERD

E

Per cent

normal

F

Difference

G

Per cent

GERD

H

Curve

fit

0.33 0 1 100 96 4 0 3

0.70 0 2 100 92 8 0 6

0.71 0 3 100 88 12 0 6

0.71 1 3 98 88 10 25 6

1.05 1 4 98 85 14 20 9

1.06 1 5 98 81 17 17 9

1.55 1 6 98 77 21 14 13

1.73 1 7 98 73 25 13 14

1.79 1 8 98 69 29 11 15

1.80 1 9 98 65 33 10 15

1.82 1 10 98 62 37 9 15

1.87 1 11 98 58 41 8 15

1.92 2 11 96 58 39 15 16

2.06 2 12 96 54 43 14 17

2.11 2 13 96 50 46 13 17

2.26 3 13 95 50 45 19 18

2.63 3 14 95 46 49 18 20

n n n n n n n n

8.1 16 23 72 12 60 41 44

n n n n n n n n

95.20 55 26 4 0 4 68 64

98.15 56 26 2 0 2 68 64

120.38 57 26 0 0 0 69 64

Column A gives results for the 24-h integrated oesophageal acidity from 26 healthy subjects

and 57 subjects with gastro-oesophageal reflux disease (GERD). To reduce the size of the table,

values indicated by n have been omitted.



values of the integrated oesophageal acidity greater

than the corresponding value of the integrated

oesophageal acidity given in column A. These

values give the sensitivity that is associated with

the corresponding value in column A.

(h) Each value in column C was divided by the total

number of normal subjects (26), subtracted from 1,

multiplied by 100 and the result recorded in the

corresponding space in column E. The values in

column E give the percentage of normal subjects

with values of the integrated oesophageal acidity

greater than the corresponding value of the integ-

rated oesophageal acidity given in column A. These

values give 100 ) specificity or the percentage of

false positives associated with the corresponding

value in column A.

(i) The values in column E were subtracted from the

corresponding values in column D and the results

recorded in column F. The largest value in column

F corresponds to the value of the integrated

oesophageal acidity in column A that gives the

optimal sensitivity and specificity. In this study, this

value of the integrated oesophageal acidity was

8.1 mmol.h/L.

(j) The value in column B was divided by the sum of

the corresponding values in columns B and C,

multiplied by 100 and the result recorded in

column G. The values in column G give the

percentage of subjects with GERD, or the positive

predictive value, at each value of the integrated

oesophageal acidity given in column A. The values

in column C can also be used to calculate the

negative predictive value.

(k) The values in column H represent the best fit of the

values in column G as a function of the values in

column A using the equation Y ¼ Ymax(1 ) e– KX),

where Ymax ¼ 63.8 [62.1, 65.5], K ¼ 0.1454

[0.1333, 0.1575] and R2 ¼ 0.958 (see Figure A1).

Values in square brackets give the 95% confidence

interval.

00

1020

20

3040

40

5060

60

7080

80

90100

100 120Column A Column E Column A

Co

lum

n D

GE

RD

(%)


Rec

ord

ing

s w

ith

Inte

gra

ted

Oes

op

hag

eal

Aci

dit

y A

bo

ve V

alu

e o

n X

-axi

s (%

)

GERD - ColumnD Normal - Column E

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Normal (%)

Probability of GERD with Different Values forIntegrated Oesophageal Acidity

0102030405060708090

100


Co

lum

n G

Pro

bab

ility

of

GE

RD

(%

)

0 20 40 60 80 100 120

Figure A1. Graphs of values in Table A1. Left panel. The values in columns D and E are plotted on the Y-axis as a function of the

corresponding value in column A on the X-axis. These graphs give the cumulative distributions of the values of the integrated

oesophageal acidity in gastro-oesophageal reflux disease (GERD) (column D) and normal (column E) subjects. Middle panel. The values for

GERD subjects in column D are plotted on the Y-axis as a function of the corresponding value for normal subjects in column E on

the X-axis. This plot gives the receiver operating characteristic curve. The values in column E are plotted on the Y-axis as a function of the

corresponding value in column E on the X-axis. This plot gives the identity line. Right panel. The values in column G are plotted on the

Y-axis as a function of the corresponding value in column A for the integrated oesophageal acidity on the X-axis. This plot gives the

probability of GERD (or the positive predictive value) for each value of the integrated oesophageal acidity. The full line is the best-fit

equation whose parameter values are given in item (k) (see text).



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