histological effects of esomeprazole therapy on the squamous epithelium of the distal oesophagus

Histological effects of esomeprazole therapy on the squamousepithelium of the distal oesophagusM. VIETH* , M. KULIG� , A . LEODOLTER� , E . NAUCLER§, D. JASPERSEN– , J . LABENZ** ,

W. MEYER-SABELLEK�� , T . L IND§, S . WILLICH� , P . MALFERTHEINER� & M. STOLTE*

*Institute of Pathology, Klinikum

Bayreuth, Bayreuth, Germany;

�University Hospital, Charite, Berlin,

Germany; �Department of Gastroen-

terology and Hepatology, Otto-von-

Guericke University, Magdeburg, Ger-

many; §AstraZeneca R&D Molndal,

Sweden; –Department of Medicine II,

Klinikum Fulda, Fulda, Germany;

**Ev.-Jung-Stilling Krankenhaus,

Siegen, Germany; ��AstraZeneca

GmbH, Wedel, Germany

Correspondence to:

Dr M. Vieth, Institute of Pathology,

Klinikum Bayreuth, 95445 Bayreuth,

Germany.

E-mail: vieth.lkpathol@uni-

bayreuth.de

Publication data

Submitted 1 August 2005

First decision 17 August 2005

Resubmitted 25 October 2005

Accepted 26 October 2005

SUMMARY

BackgroundProton pump inhibitor therapy has been reported to reduce proliferativechanges of the oesophagus significantly in gastro-oesophageal refluxdisease (GERD).

AimTo assess the histological effects of esomeprazole treatment on the oeso-phagus.

MethodsData were derived from a subgroup of patients participating in the pro-GERD study, who had either erosive reflux disease (n ¼ 720) or non-erosive reflux disease (n ¼ 35) and who had biopsy data from two sites[(i) 2 cm above the z-line and (ii) at the z-line], obtained at baselineand following treatment with esomeprazole. Proliferative changes of thesquamous epithelium were assessed histologically by measuring thick-ness of the basal cell layer and elongation of the papillae as a percent-age of the whole epithelial thickness.

ResultsIn erosive reflux disease patients, the thickness of the basal cell layerand length of the papillae pretreatment were associated with the sever-ity of oesophagitis (P < 0.05), at both biopsy sites. After esomeprazoletreatment, baseline thickness and length of papillae were significantlyreduced (P < 0.05) at both biopsy sites in non-erosive reflux diseaseand erosive reflux disease patients (particularly those with Los Angelesgrades C and D).

ConclusionThis demonstrates a strong correlation between severity of GERD andhistological parameters. Esomeprazole therapy resulted in clear rever-sal of proliferative changes observed prior to treatment in the squa-mous epithelium at both biopsy locations.

Aliment Pharmacol Ther 23, 313–319

Alimentary Pharmacology & Therapeutics

ª 2006 Blackwell Publishing Ltd 313

doi:10.1111/j.1365-2036.2006.02752.x

INTRODUCTION

The use of hyperplasia of the basal cell layer and

elongation of the papillae in the squamous epithelium

of the distal oesophagus as histological criteria for

the diagnosis of gastro-oesophageal reflux disease

(GERD) continues to be controversial. Some authors1

have concluded that although erosions and ulcers

heal under antacid treatment, the typical proliferative

changes of the squamous epithelium in patients with

reflux disease do not regress in response to therapy

with an agent such as cimetidine. This is supported

by further evidence suggesting that changes in the

lower 2 cm of the oesophagus are ‘physiological’.2

Several other studies investigating the effect of treat-

ment with antacids or H2-receptor antagonists

(H2RAs) on the histological changes of the squamous

epithelium produced similar results.3, 4 On account of

its low sensitivity compared with endoscopy, histo-

logical assessment of treatment effects in GERD has

not often been carried out in clinical studies.5 Mem-

bers of our group have recently been able to show

that, in contrast with ranitidine, short-term treatment

with a proton pump inhibitor (PPI) may reverse pro-

liferative changes of the squamous epithelium.6 This

effect can be increased by applying long-term PPI

therapy.7 In this earlier study, however, only the

effects within 2 cm above the z-line, but not exactly

at the z-line, were investigated since epithelial chan-

ges within the distal 2 cm are described as physiolo-

gical.2 In the current study, the histological changes

of the squamous epithelium at the z-line and 2 cm

above the gastro-oesophageal junction were investi-

gated in GERD patients, both prior to and after

4 weeks, treatment with esomeprazole. We were also

interested to assess whether or not there was a rela-

tionship between the histological parameters and the

severity of reflux disease, as defined by the Los

Angeles (LA) classification.

MATERIALS AND METHODS

Study design

The progastro-oesophageal reflux disease (ProGERD)

study is a prospective, multicentre, open, cohort

study currently being conducted in Germany, Austria

and Switzerland, in which patients with symptoms

suggestive of GERD are being followed up for 5 years

after receiving a healing course of therapy with eso-

meprazole. Accordingly, the trial consists of an initial

healing phase when the patients received active treat-

ment with esomeprazole and a subsequent epidemio-

logical follow-up phase of 5 years under the routine

care of a primary care physician. The study was

approved by local ethics committees within the coun-

tries, and all patients provided written informed con-

sent. Specific details regarding patient symptoms,8

exact ProGERD trial methodology,9 risk factors and

quality of life,10, 11 as well as analyses regarding

extraoesophageal symptoms12 and Helicobacter sta-

tus,13 have been previously published elsewhere.

Study patients

The study cohort is a sample of patients with symp-

toms of GERD who were recruited from hospital endo-

scopy clinics or from specialized endoscopy units,

where they were endoscoped with the objective of dis-

tinguishing between erosive and non-erosive reflux

disease (ERD and NERD respectively). Patients were

included in the ProGERD study if they met the follow-

ing entry criteria: male or female patients over

18 years whose main symptom was heartburn and

who were classified at endoscopy as having either

NERD or ERD. Individuals with Barrett’s epithelium

(without neoplastic findings) were also allowed to

enter the ProGERD programme but could only be

included in this analysis if squamous epithelium of the

distal oesophagus was present in the biopsies. Patients

were excluded if they had had continuous treatment

with any acid-suppressive drug for more than 7 days

within the 4 weeks prior to inclusion or if they had a

history of gastrointestinal surgical intervention proce-

dures (except simple closure of an ulcer) and/or gas-

tro-oesophageal malignancies. Further exclusion

criteria were contraindications to the study drugs,

pregnancy and lactation; and any ‘alarm symptoms’ or

any other signs indicating serious or malignant disease

as well as other significant cardiovascular, pulmonary,

renal, pancreatic or liver disease likely to interfere

with study procedures. For the present analysis, a sub-

sample of 755 patients (35 NERD, 720 ERD) has been

analysed. These patients had been treated for at least

24 days and were biopsied at baseline and after

4 weeks (i.e. within 24–36 days after the start of

therapy but not more than 7 days after the end of

treatment) at two sites: (i) 2 cm above the z-line

and (ii) exactly at the gastro-oesophageal junction

(Figure 1).

314 M. VIETH et al.

ª 2006 Blackwell Publishing Ltd, Aliment Pharmacol Ther 23, 313–319

Study treatment

During the initial healing phase, NERD patients received

20 mg esomeprazole o.d. for up to 4 weeks while ERD

patients received 40 mg esomeprazole o.d. for up to

8 weeks. Treatment with any acid-suppressive drug

(PPIs, H2RAs, prokinetics, sucralfate or antacids) was

terminated at least one week before initiation of study

medication and no treatment with acid-suppressive

drugs (other than study medication) or Helicobacter py-

lori eradication therapy was permitted during the initial

healing phase of the ProGERD study. However, other

medication considered necessary for the patient’s safety

and well being was allowed. After the healing phase,

patients will be followed up under routine care for

5 years and treated when required, according to the

investigator’s discretion.

Outcome measurements

Endoscopy and biopsies

Endoscopies and biopsies were performed at baseline

prior to the start of therapy and after 4 weeks in

patients with ERD. For NERD patients participating in

the ProGERD study, the assessment was planned only

at baseline, although in some cases of NERD (n ¼ 35),

endoscopy was also performed after 4 weeks, thus pro-

viding limited data for this analysis.

The LA endoscopic classification system14, 15 was

used, but, because there is no precise term for mucosal

break in German, the definition of mucosal injury was

slightly modified in the ProGERD study (mucosal

injury was defined as an area of slough with a sharp

line of demarcation from adjacent normal mucosa

rather than as a mucosal break). Erosive reflux disease

patients were graded from A to D using this definition

of a mucosal break, while NERD patients were identi-

fied by the presence of heartburn in the absence of

mucosal breaks.

At endoscopy, two biopsies were taken each from

the antrum and the corpus for H. pylori detection and

histological gastritis grading according to the updated

Sydney system.16 Biopsies were taken laterally from

the distal oesophagus 2 cm above the z-line, from nor-

mal looking squamous epithelium (but not from the

lesion itself) and, optionally, from the z-line itself.

Histological methods and grading

The biopsies obtained from the oesophagus were fixed

in 4% buffered formalin, dehydrated in an increasing

series of alcohols and xylol and embedded in paraffin.

Prior to embedding, the specimen was oriented in such

a manner that histological sectioning was carried out

perpendicular to the plane of the mucosal surface.

After deparaffinization, the 4-lm thick sections (at

least eight sections per paraffin block) were stained

with haematoxylin and eosin. Qualitative and quanti-

tative evaluation of the histological sections obtained

from the lower oesophagus was carried out as follows:

proliferative characteristics of the squamous epithe-

6509 Patients recruited

247 Excluded due to major protocol violations

NERD ERD

2970 3245 Biopsies at baseline

2935 2525 Biopsies at baseline but not at 4 weeks

35 720 Study subsample - biopsies at baseline

and 4 weeks*

* From oesophagus 2 cm above and at z-line

Figure 1. Overview of the pro-GERD study population andthe subsample used for thepresent analysis.

EFFECT OF ESOMEPRAZOLE ON OESOPHAGEAL HISTOLOGY 315


lium were assessed by calculating the thickness of the

basal cell layer and the elongation of the papillae as a

percentage of the whole epithelial thickness,17 accord-

ing to Ismail-Beigi et al.18, 19 All slides were reviewed

independently by two pathologists (MS, MV).

Statistical methods

Data were analysed separately for each biopsy loca-

tion. The elongation of papillae and thickness of the

basal cell layer at baseline and after 4 weeks of treat-

ment are presented as means together with 95% con-

fidence intervals for ERD and NERD patient subgroups

and also for LA grade A/B and C/D oesophagitis sub-

groups. Differences in mean length of papillae and

mean thickness of basal cell layer between patients

with LA grades A/B and C/D were tested by a t-test.

The changes from baseline to after 4 weeks of treat-

ment were analysed by a paired t-test for all sub-

groups (ERD, NERD, LA grades A/B and C/D). P < 0.05

was considered statistically significant. All analyses

were performed using SAS version 8.2 software run-

ning under Windows 2000 (Cary, NC, USA).

RESULTS

The histological findings obtained from the squamous

epithelial biopsies at both sites are presented in terms

of papillary length (as % of whole epithelial thickness)

in Table 1 and basal cell layer (as % of whole epithe-

lial thickness) in Table 2. At baseline there was no sta-

tistical difference in papillae and thickness of the

basal cell layer between NERD and ERD patients due

to the differing sample size. However, the observed

mean length of papillae and mean basal cell layer

thickness were higher in ERD than in NERD patients.

Furthermore, the severity of oesophagitis assessed by

the LA classification was associated with the histologi-

cal grading (P < 0.005). The more severe the oesopha-

gitis was, the more prominent and significant the

epithelial changes were, both at the z-line and 2 cm

above the gastro-oesophageal junction. Following

4 weeks treatment with esomeprazole in both ERD and

NERD patients, there was a significant reduction in

papillary length and basal cell layer thickness. In

NERD patients, the changes were less marked at the

z-line, but at 2 cm the changes were almost the same

in NERD patients as in ERD patients (Tables 1 and 2).

The histological improvements were more marked in

patients with more severe LA grade C/D oesophagitis

(who also had worse histology at baseline) than in

those with LA grade A/B, but with a similar pattern in

both groups 2 cm above and at the z-line. The severity

of basal cell hyperplasia and elongation of papillae

was more prominent at the z-line than 2 cm above.

Thus, the difference between the two LA groups (tested

using Student’s t-test) became less significant at

4 weeks for biopsies taken from 2 cm above the z-line

and was actually non-significant at 4 weeks for biop-

sies taken at the z-line. In addition, there was no dif-

ference in the z-line biopsies, even between the ERD

and NERD patients. An estimation of abnormal histol-

ogy based on the Ismail-Beigi data,18, 19 defined as

papillae length more than 20% of total epithelial

thickness, would lead to abnormal values in 60% of

NERD patients and 69% of ERD patients. After treat-

ment, these proportions were reduced to 29% in NERD

patients and 26% in ERD patients. Interestingly, there

Table 1. Length of papillae (as % of whole epithelial thickness) at 2 cm above the z-line and at z-line

Endoscopic grading n

2 cm above z-line At z-line

Baseline, mean(95% CI)

4 weeks, mean(95% CI)



NERD 35 40.7 N.S. (32.9, 48.6) 24.3* (19.8, 28.8) 48.9* (41.5, 56.2) 34.3 N.S. (28.3, 40.3)ERD (total) 720 46.1 N.S. (44.4, 47.8) 28.3* (27.0, 29.5) 54.9* (53.2, 56.6) 32.7 N.S. (31.3, 34.1)LA grade A + B 598 44.7** (42.9, 46.6) 27.6* (26.2, 28.9) 53.9* (52.1, 55.7) 32.8 N.S. (31.3, 34.3)LA grade C + D 122 52.8** (48.3, 57.2) 31.7* (28.3, 35.2) 59.7* (55.2, 64.3) 32.4 N.S. (29.0, 35.9)

NERD, non-erosive reflux disease; ERD, erosive reflux disease; LA grade, Los Angeles grade.Student t-test * P < 0.05; ** P < 0.001; N.S. ¼ not significant, changes between baseline data and 4 weeks results are alwayssignificant with improvement concerning histological parameters of squamous epithelium.

316 M. VIETH et al.


was no statistically significant correlation between

improvements in heartburn and change of length of

papillae or thickness of the basal cell layer, either

2 cm above the z-line or at the z-line.

DISCUSSION

There is still a controversial discussion about the spe-

cificity and sensitivity of histological parameters (basal

cell hyperplasia and length of papillae) in reflux dis-

ease. We have shown that there is a strong correlation

between the severity of reflux disease and hyperplasia

of the basal cell layer and elongation of the papillae

in the squamous epithelium of the distal oesophagus.

This finding is similar when patients with NERD and

ERD are compared as well as in patients with different

severity of the erosive stage of the disease. However,

the severity of basal cell hyperplasia and elongation

of papillae was more prominent at the z-line than

2 cm above, making this a better site for biopsy.

Esomeprazole therapy decreased the severity of abnor-

mal histological variables at both biopsy sites almost

to a similar level, regardless of baseline disease sever-

ity in ERD and NERD. This observation could lead one

to the assumption that this marked improvement

should be regarded as virtual normalization of the

squamous epithelium. However, inorder to unequivo-

cally define what can be considered to be normal or

abnormal histology of the distal oesophagus, the

assumption needs to be addressed in relation to

healthy controls. Unfortunately, most of the data on

this topic were published decades ago.18, 19

Data from the literature suggest that PPI therapy

significantly improves histological changes of the squ-

amous epithelium of patients with GERD,7, 20 while

H2RAs fail to change the grade of basal hyperplasia

and elongation of papillae.6, 21 Prior to the introduct-

ion of PPIs, such a positive histological result of treat-

ment of GERD with either antacids22 or H2RAs23 has

never been reported. Despite the fact that H2RAs were

administered for a longer time period than was the

case for esomeprazole in the ProGERD study and that

they were successful in healing the mucosal lesions,

they still did not affect the observed histological chan-

ges.24, 25 It has been claimed that a normalization of

the squamous epithelium in the distal oesophagus,

including normalization of the thickness of the basal

cell layer and the length of the papillae, did not

occur.3 It should be noted, however, that in the Pro-

GERD study, separate biopsies were not obtained spe-

cifically from the tops and valleys of the longitudinal

folds in the distal oesophagus to search for possible

histological differences in these two locations, as sug-

gested in the literature.26 In view of the capacity of

esomeprazole to suppress acid, the marked improve-

ment of the histological parameters of the squamous

epithelium in the distal oesophagus 2 cm above the

z-line and exactly at the gastro-oesophageal junction

was not unexpected from a pathophysiological point

of view.27–29 However, even esomeprazole does not

affect the underlying functional mechanisms in GERD,

i.e. insufficiency of the lower oesophageal sphincter

and transient relaxations.30, 31 Improvement of basal

cell hyperplasia and length of papillae of the squa-

mous epithelium has been reported to be correlated

with the intensity of the reduction in acid secretion,6

and thus probably with the intensity of acid reflux

exactly at the z-line, so this may explain the effective-

Table 2. Basal cell layer (as % of whole epithelial thickness) at 2 cm above the z-line and at z-line

Endoscopic grading n

2 cm above z-line At z-line





NERD 35 12.7 N.S. (6.9, 18.4) 4.4* (2.8, 5.9) 17.4 N.S. (11.6, 23.1) 9.2 N.S. (4.3, 14.1)ERD (total) 720 15.7 N.S. (14.2, 17.1) 5.3* (4.7, 5.8) 23.0 N.S. (21.2, 24.7) 7.7 N.S. (6.9, 8.4)LA Grade A + B 598 14.2** (12.7, 15.6) 4.9* (4.4, 5.4) 21.2** (19.4, 23.0) 7.6 N.S. (6.8, 8.3)LA Grade C + D 122 23.0** (18.4, 27.5) 7.2* (5.0, 9.4) 31.6** (26.1, 37.1) 8.2 N.S. (6.0, 10.4)

NERD, non-erosive reflux disease; ERD, erosive reflux disease; LA grade, Los Angeles grade.Student’s t-test *P < 0.05; **P < 0.001; N.S. ¼ not significant, changes between data at baseline and 4 weeks show significantimprovement in histological parameters of the squamous epithelium.



ness of esomeprazole in ‘normalizing’ the oesophageal

mucosa. The study does, however, have some weak

points, as there was no control group without reflux

disease and no routine pH-metry for confirmation of

acid reflux. On the contrary, it is known that pH-metry

may be unremarkable in more than 30% of patients

with endoscopically negative reflux,32 and in some

patients with GERD, pH-metry may give no further

information. In our study, the diagnosis of reflux dis-

ease was done by investigators and based on the clin-

ical information such as patient’s history and

symptoms and it was performed in a large patient

sample.

For the first time we have shown that there is a

strong correlation between on one hand the severity of

the reflux disease, in terms of both presence and

severity of mucosal breaks (assessed by the LA classifi-

cation) on one hand, and the histological regenerative

parameters, basal cell hyperplasia and elongation of

the papillae. This is true regardless of whether biopsies

are taken from 2 cm above the gastro-oesophageal

junction or exactly at the z-line.

In conclusion, acidsuppressive therapy with esomep-

razole reverses basal cell hyperplasia and elongation

of the papillae in a large percentage of cases. Hence,

proliferative changes found in the distal oesophagus in

reflux patients are, contrary to reports in the literature,

markers of reflux disease and may be useful both for

diagnostic purposes, especially in patients with NERD,

as well as when assessing the effect of acid inhibition

on histological changes.

ACKNOWLEDGEMENTS

We are grateful to Dr Madeline Frame of AstraZeneca

for editorial assistance and Ola Junghard of AstraZen-

eca for statistical advice with the manuscript.

This study was sponsored by a grant from

AstraZeneca.

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histological effects of esomeprazole therapy on the squamous epithelium of the distal oesophagus

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