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Role of acid and bile reflux in development of specialised intestinal metaplasia in distal oesophagus
AWIENTARYTRACT
DIGEST 1lUfR DIS 2002;34:251-7
Role of acid and bile reflux in development of specialised intestinal metaplasia in distal G. G. A. C. M. D. A. G. M. M. L.
Zaninotto Portale Parenti’ Lanzal Costantini Molena Ruol Battaglia Costantino Epifani Nicoletti
See commentery on pages 246-E
1
Background. Barrett’s oesophagus is defined as specialised intestinal metaplasia in the distal oesophagus, regardless of extension. Aim. To study distal oesophagus function, and acid and bile exposure in patients with Long Segment (>3 cm), Short Segment (I to 2 cm) and Ultra-short Segment (
Digest
liver
Key words:
Department of Medical and Surgical Sciences, 1Oepartment of Oncological and Surgical Sciences, University of Padova, Italy. M&we fer cemepndeeee G. Zaninotto, Oipartimento di Scianze Mediche e Chirurgiche, Clinica Chirurgica IV, Univarsiti di Padova, Facolti di Medicina, via Giustinieni 2, 35128 Padova, Italy. Fax: +39-049-8213152, E-mail: zaninot@ux 1.unipd.it Study supported in pert by grant from Regiane Veneto. Submittad July 24,2001. Accepted after revision October 19, 2001.
oesophagus
Dis 2002;34:251-7 Barrett’s
oesophagus;
bile reflux;
intestinal
metaplasia
Introduction The definition of Barrett’s oesophagus has been profoundly modified in recent years: Barrett’s oesophagus is currently defined by most Authors as the presence of specialised intestinal metaplasia (SIM) in the distal oesophagus, regardless of its extension ’ 2. This condition may be further divided into: Long Segment Barrett’s Oesophagus (LSBO), when SIM is found 3 or more cm above the oesophago-gastric junction, Short Segment Barrett’s Oesophagus (SSBO) when l-2 cm of the normal squamous epithelium of the distal oesophagus are totally or partially replaced by SIM, and Ultra-Short Segment Barrett’s Oesophagus (USSBO) when SIM is found in biopsies taken immediately adjacent (~1 cm) to the squamous lining in patients with a normal-appearing z-line ’ 4. The prevalence of these conditions appears to range between 7% and 18% when biopsies are taken regularly in this region 5-7. Their clinical interest lies in the fact that most (if not all) adenocarcinomas arising in the distal oesophagus and cardia seem to develop from SIM 7 and it has been estimated that the presence of LSBO carries a 30- to 125-fold greater risk of progression to oesophageal adenocarcinoma x. However, despite the numerous studies published, the aetiology of Barrett’s oesophagus
hid/bile
reflur and intestinal metaplasia
and the relationships between the three situations (LSBO, SSBO and USSBO) are still unclear. We do not know, for example, whether LSBO develops quickly to its full extent or USSBO and SSBO are the initial steps of a progressive condition. It is also not clear whether short or ultra-short segments of intestinal metaplasia (IM) share the same aetiology as long segments: LSBO has been associated with long-standing gastro-oesophageal reflux disease, defective lower oesophageal sphincter (LES), defective oesophageal peristalsis and (probably) duodenogastric reflux 9; on the other hand, less information is available on the aetiology of SSBO and USSBO, and the role of gastro-oesophageal reflux disease (GERD) in their pathogenesis. This study was designed to investigate the role of acid and bile reflux in the development of different lengths of IM in the distal oesophagus.
Patients and methods Study population From January 1998 to June 2001, 66 patients were studied: 52 males and 14 females, with a median age of 52 years, range 24-72. They were divided into 4 groups according to the presence and extension of SIM in the distal oesophagus (Barrett’s oesophagus). The first group was composed of 17 patients with a diagnosis of Long Segment Barrett’s oesophagus (LSBO: >3 cm), 15 males and 2 females, with a median age of 56 years (range 35-72). The second group included 8 male patients with Short Segment Barrett’s oesophagus (SSBO: l-3 cm), median age 50 years, range 31-67. The third group included 9 male patients with Ultra-Short Segment Barrett’s oesophagus (USSBO:
of their gastrointestinal symptoms, particularly the severity and frequency of pain, heartburn and regurgitation. Symptom severity was assessed by means of a scale on which a symptom-free period was scored as 1 and the maximum score of 8 reflected a day when a symptom interfered with normal life. Patients were also asked about episodes of non-cardiac chest pain or pulmonary symptoms related to GERD, including coughing, wheezing and asthma. They were also questioned about any medication that might influence GERD symptoms, such as the use of histamine-2 receptor antagonists, proton pump inhibitors, nitrates, calcium channel blockers (in the month preceding the study any medication that could have affected gastrointestinal motility or secretion was stopped). Endoscopy and histology Upper gastrointestinal endoscopy was performed only in the patients. The oesophago-gastric junction (OGJ) was defined as where the tubular oesophagus widened and flared into the gastric sac; for cases with a hiatal hernia, the OGJ was defined as the proximal margin of the gastric folds. During endoscopy any oesophagitis, ulcers, strictures, hiatal hernia or Barrett’s oesophagus was recorded by the endoscopists; oesophagitis was classified according to Savary and Miller lo. Barrett’s oesophagus was suspected when a pink-coloured epithelium was observed above the OGJ; in such cases, four-quadrant biopsies were taken on the suspected metaplastic epithelium at 2 cm intervals, starting from the OGJ. Patients with IM in biopsies taken immediately adjacent (~1 cm) to the squamous lining, with a normal-appearing z-line were selected from among those taking part in a study to investigate the prevalence of this condition in our region ” 12. The specimens were fixed in 10% buffered formalin, embedded in paraffin wax and stained with haematoxylin and eosin. Barrett’s oesophagus was ultimately defined as the presence of fully-developed goblet cells in the distal oesophagus above the OGJ, regardless of their extent. The condition was further classified as Long Segment (3 cm or more), Short Segment (l-2 cm) and UltraShort Segment (O-l cm), according to the distance of the Z-line from the OGJ. Since IM has two possible patterns of mucosa secretion, one related to ileal mucosa (ileal intestinal metaplasia, complete and incomplete, with secretion of neutral and sialo-mucins) and the other similar to colonic mucosa (colonic intestinal metaplasia, incomplete, with predominant secretion of sialo- and sulphomucins), two further stainings were performed with Alcian blue pH 2.5/periodic acid-Schiff (AB pH 2.5/PAS) (PAS) (to identify neutral and acid mucins) and high iron diamine (HID) Alcian blue pH 2.5 (to
6. Zaninntto et al.
distinguish between sialo- and sulpho-mucins). Based on these stainings, intestinal metaplasia was classified as type I (goblet cells secreting sialomucins), type II (goblet cells secreting sialo- and sulpho-mucins) and type III (sulphomucins in the goblet cells) 13. Each specimen was also stained with Giemsa and examined for the presence of Helicobacter pylori (H. pylori). Manometric evaluation All subjects underwent stationary manometry to locate the LES. The manometric study was performed after fasting for 8 hours and with the patient supine. An S-lumen, water-perfused oesophageal manometry catheter assembly was used with 4 radial ports and 4 lateral ports spaced 5 cm apart. After local anaesthesia the catheter assembly was inserted through the nostril, passed into the stomach and then withdrawn through the LES using the motorised pull-through technique. Oesophageal contractions elicited by ten “wet” swallows of 10 ml of water were assessed with the distal hole of the catheter at the level of the LES and the other side-holes 5 cm apart. The LES was defined as defective if the resting pressure was below 6 mmHg or the overall length was less than 2.0 cm, or the abdominal length was less than 1 .O cm r4. The oesophageal pump function was described as defective if the amplitude or duration of the peristaltic contraction of the body of the oesophagus fell below the 5” percentile of normal subjects. Acid and bile monitoring Acid and bile exposure in the distal oesophagus was monitored using pH and bilirubin probes secured together so that the tips lay side by side, ensuring a sampling 5 cm above the upper border of the LES, detected previously by manometry. Oesophageal pH was monitored with a glass probe connected to a portable solid state monitor (Digitrapper, Medtronics, Minneapolis, MN, USA). The acid reflux parameters assessed were: the total percentage of time when the pH was ~4, the percentage of time when the pH was ~4 while upright, the percentage of time when the pH was ~4 while supine, the number of episodes with a pH ~4, the number of episodes with a pH ~4 lasting more than 5 minutes and the duration of the longest episode with a pH ~4 “. Bilirubin reflux was monitored with a fibre-optic sensor connected to a portable spectrophotometer (Bilitec 2000@, Medtronics, Synectics, Stockholm, Sweden): bilirubin has a characteristic light absorption peak at 453 nm and the presence of bilirubin is inferred from the detection of an absorption peak at this wavelength. The 0.2 absorbance threshold was taken as indicative of bile reflux (the absorbance scale ranged from 0 to 1). Since a variety of food products, such as cheese, carrots, or tomatoes, may simulate the presence of bilirubin in the
oesophagus (resulting in false-positive readings) and solid food may clog the probe tip (causing inaccurate data reading), subjects were fed with a standardised 1000 ml of banana- or vanilla-flavoured liquid diet (Nutridrink@, Nutricia, Zoetermeer, The Netherlands) with proper absorbance characteristics. Subjects were allowed home wearing two recording boxes on a waist belt and encouraged to engage in normal daily activities. Data were collected in a portable data trapper, then downloaded onto a computer and analysed in a fashion similar to pH recording. The bile reflux parameters assessed were the total percentage of time when the absorbance was >0.2, the percentage of time when the absorbance was >0.2 while upright, the percentage of time when the absorbance was >0.2 while supine, the number of episodes of the absorbance being >0.2, the number of episodes of the absorbance being >0.2 for more than 5 minutes, and the duration of the longest episode of absorbance ~0.2 16. Statistical analysis Data were expressed as median and range. The Kruskal-Wallis non-parametric test was used to assess statistical significance. If statistical significance was achieved (p
Demographic and symptom score data Patients with SIM in the distal oesophagus or OGJ were older than those without; their median age was 55 years (range: 3 l-72) as compared with 47.5 (24-72) for GERD patients without IM (~~0.05). There was no difference between the LSBO, SSBO and USSBO groups. Patients with SIM in the distal oesophagus, regardless of its length, were predominantly males, i.e., 32 males and 2 females vs 20 males and 12 females in the GERD group (~~0.01). The smoking and drinking habits of patients, and their use of medication are summarised in Table I. 253
Acid/bile reflux and intestinal metaplasia
Table 1. Demographics
and symptom
9ERD In=921
UB9B9 In=91
23.0 (21-251
47.5 (24-721
(31-681
C315:71
Sex M:F
50 (355-6721
9:o
8:O
15:2
9
15
3
1
9
12
32
9
7
14
Al
A4
A4
K 02
i: 01
Ko 01
lf81
4; ('l-81
[:81
[i-81
IO!31
12.5" (4-231
7.0 (3-I 81
10.0" (3-201
&31
-
24" (2-I 801
12 IO-1 201
24^ [O-I 801
60 (4-2401
Use of medication
i: Cl5 D8 *
Heartburn score
Duration of symptoms
LOB0 In=171
20:12
Alcohol intake ~50 g/day
score
SSBO In=91
57
Smoking Cl 0 cigarettes/day
Overall symptom
data.
In=121
cantds
Age
score
in months
*,n
'
’ ~~0.05 vs control subjects; n ~~0.05 vs USSBO patients. expressed as median and range lin brackets]. Abbreviations:
Table II. Manometric
data
Resultes are see list.
ILESI.
In=121
GERD k321
Resting pressure in mmHg
16.5 (7-331
12" (2-351
I:-:61
Abdominal length in mm
28.5 (13-351
25" (8-691
32 [l&441
23.5" (19-391
16^"§ (5-421
Total length in mm
42.5 (28-471
42.5" (21-791
50 (25-601
36" (30-521
32"'§ (14-521
cenlrals
II9990
s999
In=91
In=91
LS99 he171
IO (6-I 81
6.5"*" (4-201
'
* ~~0.05 vs control subjects; ’ ~~0.05 vs SSBOAJSSBO patients; § pcO.05 vs GERO patients. Results are expressed as median and range Il. Abbreviations: see list.
lble III. Intestinal
Manometric data The median LES resting pressure in the patients was lower than in controls. LSBO patients had the lowest LES resting pressure. No difference was observed between SSBO or USSBO and GERD as regards LES manometric characteristics (Table II). LES was defective in 8 out of 17 (47%) LSBO, 1 out of 8 (13%) SSBO, none of 9 USSBO, and 5 out of 32 (16%) GERD patients. The amplitude of the oesophageal contractions was significantly lower in LSBO (median 53.5 mmHg, range: 27-l 12) than in the control group (median 83 mmHg, range: 45-171) (p
metaplasia.
We
I
II
III
LSBO SSBO
2 0
5
8
USSBO Total
3
1 1
4 1
5
7
13
* In 4 cases I2 LISSBO and 2 SSBO patients1 tinguish the type of intestinal metaplasia.
254
The main symptoms were heartburn (40/66: 70%), belching (31/66: 47%), and retrosternal pain (30/66: 45%). In 26 out of 66 patients (40%), the symptoms were severe enough to interfere with daily activities, work or social life (symptom score >14). There was no difference in the overall symptom scores for the four groups of patients; LSBO patients had a higher score for heartburn (~~0.05) than the other groups, however, and a longer history of symptoms (Table I).
it was impossible
-
TabIs IY H. py/ori
H. pylori+ infection
infection.
GE66 hl=321
6B666 tdl
7132 [22%1
219
O/8
4/17
[22%1
[O%l
(23%)
to disAbbreviations:
see list.
6666 k61
C. Zaninotto et al.
Table
U. Twenty-four hour pH monitoring data
2% = s:, 99999 l9no In=91
Total time pH <4
z
In=l7~
0.1 4.5'" 1.7" 5" 12.8*""" KLO-1.51 fO.l-37.51 fO.l-4.71 fO.5-14.31 [I .5-66.11
Upright time 0.2 4.3"" 2.4" pH <4 (0.0-2.31 [0.2-41.21 [0.2-7.31
2.4" (0.4-5.81
8.8*05" (0.9-801
Supine time pH <4
0.0 (0.0-0.81
2.6' (O-311
0.6 (0.0~5.61
6.7' 13.3'""" [O-30.81 f2.3-49.31
Totaln. acid episodes
3.5 co-21I
25""" H-2831
16" 12-341
23* (g-341
72~s~ [20-2001
Acid refluxes lasting more than 5 min
0.0 CO-01
3’” (O-201
1.o* (O-51
3.5" (O-71
1OGO§ CO-261
Longest acid reflux episode fminl
1.0 (O-51
14@ II-1451
6.0* U-361
16.5' (1-1111
(3-1871
28”“§”
* p
Acid exposure in the distal oesophagus Patients with IM in the distal oesophagus had a greater exposure to acid gastric contents than controls. However, patients with LSBO had a longer exposure time at pH ~4 than all the other groups. The results for acid exposure are shown in Table V. On a single-patient basis, a positive 24-hour pH monitoring test result was found in 78% of patients with GERD, 30% of patients with USSBO, 75% of patients with SSBO and 94% of patients with LSBO. Bile exposure in distal oesophagus Exposure to bile in the distal oesophagus was significantly greater in the LSBO patients than in any of the other groups, while no difference was observed between GERD, SSBO and USSBO patients, or between SSBO and USSBO patients and controls (Fig. 1). Results of the logistic regression test are shown in Table VI. The presence of bile, a low resting pressure of the LES, age and sex were the variables that entered the model and predicted the presence of LSBO with a probability of 83%.
Odds retio
0
:
*
0
T
al
Confidence
&nits
Total bile exposure LES resting pressure
The probability of developing increasingly lengthy IM in the distal oesophagus (USSBO, SSBO or LSBO) rose by 10% for each 3% increment in total bile exposure, by 36% for a 3 mmHg reduction in LES resting pressure and by 33% for an additional 10 years of age. Male sex was associated with a 48 times greater risk of developing IM.
Discussion Controls
GERD
USSBO
SSBO
LSBO*
Fip. X24-hour bile exposure in distal oesophagus in patients with long segment Barrett’s oesophagus ILSBOI, short segment Barrett’s oesophagus [SSBOI , ultra-short segment Barrett’s oesophagus MiSBOI , gastro-oesophageal reflux disease [GEROI and in controls [healthy volunteers). Patients with LSBO have longer exposure to bile in their distal oesophagus than all other groups. *p
The results of this study confirm that the extensive replacement of the squamous epithelium of the distal oesophagus with intestinal-type “goblet” cells (specialised intestinal metaplasia), i.e., the so-called LSBO, is the direct consequence of long-standing, severe GERD. The patients affected are older than patients with uncomplicated GERD, they have higher scores for heartburn (the most typical symptom of GERD), and
Acid/bile reflun and intestinal metaplasia
median duration of their symptoms was of 5 years, i.e., twice as long as in patients with uncomplicated GERD. The LES of these patients is scarcely competent, mainly because of a low resting pressure and a short abdominal segment; a defective LES is found three times more often in LSBO than in GERD patients. Due to this LES incompetence, patients with LSBO are more prone to their distal oesophagus being exposed to acid gastric juices for longer periods, especially at night, when the patient lies down and the protective effect of gravity is absent. Although a clear difference in oesophageal motility between the four patient groups was not demonstrated, a lower amplitude of oesophageal contractions was observed in LSBO patients than in controls (however, our controls were also younger than the patients). LSBO patients also had longer single episodes of acid reflux and more reflux episodes lasting more than 5 minutes than the other patient groups, confirming that their oesophageal clearance had deteriorated Is. However, oesop h ag eal acid exposure alone is not sufficient to explain why long segments of IM develop only in certain patients with severe GERD and several aspects of the pathogenesis of Barrett’s oesophagus are still not clear. Two key questions remain to be answered. First, what are the relationships between LSBO, SSBO and USSBO? Second, which noxious agent(s) can induce the progressive intestinalisation of the oesophageal epithelium? Some Authors claim that USSBO should be considered as a totally different disease from true Barrett’s oesophagus and they have reported no association with erosive oesophagitis, but a positive association with H. pylori infection and with mucosal atrophy and metaplasia in other segments of the stomach 19. It was, therefore, argued that USSBO should be considered as an extension of gastritis rather than as a part of reflux disease. Further evidence, in favour of this theory, lies in the observation that patients with LSBO, SSBO and USSBO are of comparable median age, both in the present study and in others 20, thus suggesting a different mechanism. After careful physiological studies, DeMeester and DeMeester 2o have hypothesised a totally different pathogenesis. The so-called two-step theory has been formulated, according to which all LSBO derive from SSBO or USSBO. The first step consists in the creeping replacement of the cardiac mucosa with intestinal-type cells. The cardia region is the furthest away from the stomach and it is the area most likely to be exposed to a pH of 3 to 5 due to the dilution and neutralisation of refluxed acid by the saliva: the exposure of columnar epithelial cells to a pH of 3 to 5 has been shown to encourage the development of IM 21. This process also induces inflammatory changes in the muscular-is propria of the LES and leads to a progressive deterioration in the intrinsic tone of the LES; this will ultimately lead to a 256
greater quantity of gastric contents penetrating the distal oesophagus and further damaging the oesophageal mucosa, eventually causing extensive substitution by specialised IM (second step). This theory has been supported by Loughney et al. 21, who demonstrated a greater acid exposure in patients with SSBO by monitoring the pH 5 cm above the LES; these patients also revealed an increased acid exposure at LES level, though this was not statistically significant compared to normal subjects. The “two-step” theory is supported only in part by data emerging from in this study: patients with LSBO were not older, but they did have a longer history of symptomatic reflux disease than all the other groups; all three groups with intestinal-type metaplasia (LSBO; SSBO and USSBO) had a greater acid exposure in the distal oesophagus than healthy controls and the total acid exposure time increased progressively from USSBO to LSBO. It might be argued that the healthy subjects, in the present study, probably had a very low acid exposure because of their younger age. Acid exposure is generally little affected by age, however 2223, and the low exposure of the healthy control group in this study is probably due to the liquid diet administered during bile and pH monitoring, with ingredients that do not interfere with bile absorbance - a diet that can hardly be considered as physiological and that probably reduces the physiological number of reflux episodes and their duration. Given that patients were fed the same diet as controls, the different results obtained were considered reliable. However, when examining data on a single-patient basis, the majority of patients with USSBO did not have abnormal acid exposure in their distal oesophagus and the development of focal islands of intestinal metaplasia cannot be explained by abnormal acid exposure alone. Indeed, a more distinct correlation is observed between abnormal 24-hour pH monitoring, SSBO and LSBO: it seems more likely that these two abnormalities are both related to excessive acid exposure in the distal oesophagus and SSBO (but not USSBO) is probably the precursor of LSBO. Why do long segments of intestinal metaplasia only develop in a minority of patients with GERD? Does bile play a part in this process? The results of the present study provide further evidence of the involvement of bile: the proportion of time with exposure to bile was more than 4 times higher in patients with LSBO than in those with GERD. During the night, while patients are supine, the distal oesophagus with LSBO is bathed in bile for nearly 20% of the time. Moreover, the presence of long segments of IM was predicted with an 83% probability by four variables used in a model constructed with the logistic regression test, i.e. the presence of bile, LES resting pressure, age and sex. However, this study cannot rule out the possibility that bile is merely secondary to excessive acid exposure (the more the gastric contents flow back into the gullet,
C. Zaninotto et al.
the easier it is to detect bile), but some interesting experimental trials have shown that bile is directly capable of differentiating cell cultures towards IM 24. In any case, bile is feasibly not the only cause of the onset of LSBO: genetic factors linked to the white race and the male sex, and smoking and drinking habits are probably also implicated. No clear interpretation linking different types of IM to different extensions of Barrett’s oesophagus or different types of reflux (acid or acid plus bile) has been found as yet and this aspect of the disease needs further investigation. Longitudinal studies are also required to confirm the hypothesis that SSBO is the precursor of LSBO. The results of this study would also suggest some therapeutic implications: LSBO patients have the most severe GERD and it has been demonstrated that acid reflux persists in most of these patients despite adequate symptom control with appropriate antisecretory drugs 25. Such medication also fails to prevent bile reflux so, with medication alone, the two causes of LSBO (acid and bile reflux in the distal oesophagus) will persist and the disease will more than likely progress. The surgical option of fundoplication should consequently be considered in these patients. List of abbreviations In Tables: Controls: healthy volunteers: A: antiacids; B: histamine 2-receptor antagonists; C: proton pump inhibitors: D: prokinetics. GERD: gastro-oesophageal reflux disease; H. py/ori: Helicobacter py/ori; HID: high iron diamine; HV: healthy volunteers; IM: intestinal metaplasia; LES: lower oesophageal sphincter; LSBO: Long Segment Barrett’s Oesophagus; OGJ: oesophago-gastric junction PAS: periodic acid-Schiff; SIM: specialised intestinal metaplasia; SSBO: Short Segment Barrett’s Oesophagus; LISSBO: Ultra-Short Barrett’s Oesophagus.
References ’ Haggitt RC. Barrett’s esophagus, dysplasia and adenocarcinoma. Hum Path01 1994;25:982-3. ’ Gottfried MR, McClave SA, Boyce HW. Incomplete intestinal metaplasia in the diagnosis of columnar lined esophagus (Barrett’s esophagus). Am J Clin Path01 1989;92:741-6. 3 Weston AP, Krmpotich P, Makdisi WF, Cherian R, Dixon A, McGregor DH, et al. Short segment Barrett’s esophagus: clinical and histological features, associated endoscopic findings and association with gastric intestinal metaplasia. Am J Gastroenterol 1996;91:982-6. ’ Nandurkar S, Talley NJ. Barrett’s esophagus: the long and the short of it. Am J Gastroenterol 1999;94:30-40. ’ Morales TG, Sampliner RE, Bhattacharyya A. Intestinal metaplasia of the gastric cardia. Am J Gastroenterol 1997;92:414-8. 6 Spechler SJ, Zeerogian JM, Antonioli DA, Goyal RK. Prevalence of metaplasia at the gastroesophageal junction. Lancet 1994;344:
1533-6.
7 Ruol A, Parenti AR, Zaninotto G, Merigliano S, Costantini M, et al. Intestinal metaplasia is the probable common precursor of
adenocarcinoma in Barrett’s esophagus and adenocarcinoma of the gastric cardia. Cancer 2000;88:2520-8. 8 Provenzale D, Kemp JA, Arora S, Wong JB. A guide for surveillance of patients with Barrett’s esophagus. Am J Gastroenterol 1994;89:670-80. y Oberg S, DeMeester TR, Peters JH, Hagen JA, Nigro JJ, De Meester S, et al. The extent of Barrett’s esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure. J Thorac Cardiovasc Surg 1999; 117:572-82. lo Savary M, Miller G. L’oesophage. Manuel et atlas d’endoscopie. Solothurn: Gassmann; 1977. ‘I Zaninotto G, and the G.I.S.U. Prevalence of intestinal metaplasia in the distal oesophagus, oesophagogastric junction and gastric cardia in symptomatic patients in North-East Italy: a prospective, descriptive survey. Digest Liver Dis 200 1;33:3 16-2 1. Iz Fireman Z, Wagner G, Weissman J, Kopelman Y, Wagner Y, Groissman G, et al. Prevalence of short-segment Barrett’s epithehum. Digest Liver Dis 2001;33:322-5. I3 Filipe Ml, Munoz N, Matko I, Kato I, Pompe-Kirn V, Juterserk A, et al. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. lnt J Cancer 1994;57:324-9. I4 Passaretti S, Zaninotto G, Di Martin0 N, Leo P, Costantini M, Baldi F. Standards for oesophageal manometry. A position statement from the Gruppo Italian0 di Studio Motilita Apparato Digerente (GISMAD) Digest Liver Dis 2000;32:46-55. Is Jamieson JR, Stein HJ, DeMeester TR, Bonavina L, Schwizer W, Hinder RA, et al. Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity and reproducibility. Am J Gastroenterol 199287: 104- 11. Ih Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. The need for surgical therapy re-emphasized. Ann Surg 1995;222:525-33. ” Hosmer DW Lemeshow S. Applied logistic regression. New York: Wiley;‘1989. ” Zaninotto G, DeMeester TR, Bremner CG, Smirk TC, Cheng SC. Esophageal function in patients with reflux induced stricture and its relevance to surgical treatment. Ann Thorac Surg 1989;47:362-70. ” El-Serag HB, Sonnenberg A, Jamal MM, Kunkel D, Crooks L, Feddersen RM. Characteristics of intestinal metaplasia in the gastric cardia. Am J Gastroenterol 1999;94:622-7. ” DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus. Fifty years of controversy. Ann Surg 2000;3:303-21. ” Loughney T, Maydonovitch CL, Wong RKH. Esophageal manometry and ambulatory 24-hour pH monitoring in patients with short and long segment Barrett’s esophagus. Am J Gastroenterol 1998;93:916-9. 2? Richter JE, Bradley LA, De Meester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age and gender. Dig Dis Sci 1992;37:849-56. ” Ortiz A, Martinez de Haro LF, Parrilla P, Molina J, Bermejo J, Munitz V. 24-h pH monitoring is necessary to assess acid reflux suppression in patients with Barrett’s oesophagus undergoing treatment with proton pump inhibitors. Br J Surg 1999;86: 1472-4. I4 Ransford RAJ, Jankowsky JAZ. Genetic versus environmental interactions in the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence (MCS) of Barrett’s esophagus. Acta Gastroenterol Belg 2000;63: 18-21. *’ Stein HJ, Kauer WKH, Feussner H, Siewert JR. Bile reflux in benign and malignant Barrett’s esophagus: effect of medical acid suppression and Nissen fundoplication J Gastrointest Surg 1998;2:333-41.
257
DIGEST 1lUfR DIS 2002;34:251-7
Role of acid and bile reflux in development of specialised intestinal metaplasia in distal G. G. A. C. M. D. A. G. M. M. L.
Zaninotto Portale Parenti’ Lanzal Costantini Molena Ruol Battaglia Costantino Epifani Nicoletti
See commentery on pages 246-E
1
Background. Barrett’s oesophagus is defined as specialised intestinal metaplasia in the distal oesophagus, regardless of extension. Aim. To study distal oesophagus function, and acid and bile exposure in patients with Long Segment (>3 cm), Short Segment (I to 2 cm) and Ultra-short Segment (
Digest
liver
Key words:
Department of Medical and Surgical Sciences, 1Oepartment of Oncological and Surgical Sciences, University of Padova, Italy. M&we fer cemepndeeee G. Zaninotto, Oipartimento di Scianze Mediche e Chirurgiche, Clinica Chirurgica IV, Univarsiti di Padova, Facolti di Medicina, via Giustinieni 2, 35128 Padova, Italy. Fax: +39-049-8213152, E-mail: zaninot@ux 1.unipd.it Study supported in pert by grant from Regiane Veneto. Submittad July 24,2001. Accepted after revision October 19, 2001.
oesophagus
Dis 2002;34:251-7 Barrett’s
oesophagus;
bile reflux;
intestinal
metaplasia
Introduction The definition of Barrett’s oesophagus has been profoundly modified in recent years: Barrett’s oesophagus is currently defined by most Authors as the presence of specialised intestinal metaplasia (SIM) in the distal oesophagus, regardless of its extension ’ 2. This condition may be further divided into: Long Segment Barrett’s Oesophagus (LSBO), when SIM is found 3 or more cm above the oesophago-gastric junction, Short Segment Barrett’s Oesophagus (SSBO) when l-2 cm of the normal squamous epithelium of the distal oesophagus are totally or partially replaced by SIM, and Ultra-Short Segment Barrett’s Oesophagus (USSBO) when SIM is found in biopsies taken immediately adjacent (~1 cm) to the squamous lining in patients with a normal-appearing z-line ’ 4. The prevalence of these conditions appears to range between 7% and 18% when biopsies are taken regularly in this region 5-7. Their clinical interest lies in the fact that most (if not all) adenocarcinomas arising in the distal oesophagus and cardia seem to develop from SIM 7 and it has been estimated that the presence of LSBO carries a 30- to 125-fold greater risk of progression to oesophageal adenocarcinoma x. However, despite the numerous studies published, the aetiology of Barrett’s oesophagus
hid/bile
reflur and intestinal metaplasia
and the relationships between the three situations (LSBO, SSBO and USSBO) are still unclear. We do not know, for example, whether LSBO develops quickly to its full extent or USSBO and SSBO are the initial steps of a progressive condition. It is also not clear whether short or ultra-short segments of intestinal metaplasia (IM) share the same aetiology as long segments: LSBO has been associated with long-standing gastro-oesophageal reflux disease, defective lower oesophageal sphincter (LES), defective oesophageal peristalsis and (probably) duodenogastric reflux 9; on the other hand, less information is available on the aetiology of SSBO and USSBO, and the role of gastro-oesophageal reflux disease (GERD) in their pathogenesis. This study was designed to investigate the role of acid and bile reflux in the development of different lengths of IM in the distal oesophagus.
Patients and methods Study population From January 1998 to June 2001, 66 patients were studied: 52 males and 14 females, with a median age of 52 years, range 24-72. They were divided into 4 groups according to the presence and extension of SIM in the distal oesophagus (Barrett’s oesophagus). The first group was composed of 17 patients with a diagnosis of Long Segment Barrett’s oesophagus (LSBO: >3 cm), 15 males and 2 females, with a median age of 56 years (range 35-72). The second group included 8 male patients with Short Segment Barrett’s oesophagus (SSBO: l-3 cm), median age 50 years, range 31-67. The third group included 9 male patients with Ultra-Short Segment Barrett’s oesophagus (USSBO:
of their gastrointestinal symptoms, particularly the severity and frequency of pain, heartburn and regurgitation. Symptom severity was assessed by means of a scale on which a symptom-free period was scored as 1 and the maximum score of 8 reflected a day when a symptom interfered with normal life. Patients were also asked about episodes of non-cardiac chest pain or pulmonary symptoms related to GERD, including coughing, wheezing and asthma. They were also questioned about any medication that might influence GERD symptoms, such as the use of histamine-2 receptor antagonists, proton pump inhibitors, nitrates, calcium channel blockers (in the month preceding the study any medication that could have affected gastrointestinal motility or secretion was stopped). Endoscopy and histology Upper gastrointestinal endoscopy was performed only in the patients. The oesophago-gastric junction (OGJ) was defined as where the tubular oesophagus widened and flared into the gastric sac; for cases with a hiatal hernia, the OGJ was defined as the proximal margin of the gastric folds. During endoscopy any oesophagitis, ulcers, strictures, hiatal hernia or Barrett’s oesophagus was recorded by the endoscopists; oesophagitis was classified according to Savary and Miller lo. Barrett’s oesophagus was suspected when a pink-coloured epithelium was observed above the OGJ; in such cases, four-quadrant biopsies were taken on the suspected metaplastic epithelium at 2 cm intervals, starting from the OGJ. Patients with IM in biopsies taken immediately adjacent (~1 cm) to the squamous lining, with a normal-appearing z-line were selected from among those taking part in a study to investigate the prevalence of this condition in our region ” 12. The specimens were fixed in 10% buffered formalin, embedded in paraffin wax and stained with haematoxylin and eosin. Barrett’s oesophagus was ultimately defined as the presence of fully-developed goblet cells in the distal oesophagus above the OGJ, regardless of their extent. The condition was further classified as Long Segment (3 cm or more), Short Segment (l-2 cm) and UltraShort Segment (O-l cm), according to the distance of the Z-line from the OGJ. Since IM has two possible patterns of mucosa secretion, one related to ileal mucosa (ileal intestinal metaplasia, complete and incomplete, with secretion of neutral and sialo-mucins) and the other similar to colonic mucosa (colonic intestinal metaplasia, incomplete, with predominant secretion of sialo- and sulphomucins), two further stainings were performed with Alcian blue pH 2.5/periodic acid-Schiff (AB pH 2.5/PAS) (PAS) (to identify neutral and acid mucins) and high iron diamine (HID) Alcian blue pH 2.5 (to
6. Zaninntto et al.
distinguish between sialo- and sulpho-mucins). Based on these stainings, intestinal metaplasia was classified as type I (goblet cells secreting sialomucins), type II (goblet cells secreting sialo- and sulpho-mucins) and type III (sulphomucins in the goblet cells) 13. Each specimen was also stained with Giemsa and examined for the presence of Helicobacter pylori (H. pylori). Manometric evaluation All subjects underwent stationary manometry to locate the LES. The manometric study was performed after fasting for 8 hours and with the patient supine. An S-lumen, water-perfused oesophageal manometry catheter assembly was used with 4 radial ports and 4 lateral ports spaced 5 cm apart. After local anaesthesia the catheter assembly was inserted through the nostril, passed into the stomach and then withdrawn through the LES using the motorised pull-through technique. Oesophageal contractions elicited by ten “wet” swallows of 10 ml of water were assessed with the distal hole of the catheter at the level of the LES and the other side-holes 5 cm apart. The LES was defined as defective if the resting pressure was below 6 mmHg or the overall length was less than 2.0 cm, or the abdominal length was less than 1 .O cm r4. The oesophageal pump function was described as defective if the amplitude or duration of the peristaltic contraction of the body of the oesophagus fell below the 5” percentile of normal subjects. Acid and bile monitoring Acid and bile exposure in the distal oesophagus was monitored using pH and bilirubin probes secured together so that the tips lay side by side, ensuring a sampling 5 cm above the upper border of the LES, detected previously by manometry. Oesophageal pH was monitored with a glass probe connected to a portable solid state monitor (Digitrapper, Medtronics, Minneapolis, MN, USA). The acid reflux parameters assessed were: the total percentage of time when the pH was ~4, the percentage of time when the pH was ~4 while upright, the percentage of time when the pH was ~4 while supine, the number of episodes with a pH ~4, the number of episodes with a pH ~4 lasting more than 5 minutes and the duration of the longest episode with a pH ~4 “. Bilirubin reflux was monitored with a fibre-optic sensor connected to a portable spectrophotometer (Bilitec 2000@, Medtronics, Synectics, Stockholm, Sweden): bilirubin has a characteristic light absorption peak at 453 nm and the presence of bilirubin is inferred from the detection of an absorption peak at this wavelength. The 0.2 absorbance threshold was taken as indicative of bile reflux (the absorbance scale ranged from 0 to 1). Since a variety of food products, such as cheese, carrots, or tomatoes, may simulate the presence of bilirubin in the
oesophagus (resulting in false-positive readings) and solid food may clog the probe tip (causing inaccurate data reading), subjects were fed with a standardised 1000 ml of banana- or vanilla-flavoured liquid diet (Nutridrink@, Nutricia, Zoetermeer, The Netherlands) with proper absorbance characteristics. Subjects were allowed home wearing two recording boxes on a waist belt and encouraged to engage in normal daily activities. Data were collected in a portable data trapper, then downloaded onto a computer and analysed in a fashion similar to pH recording. The bile reflux parameters assessed were the total percentage of time when the absorbance was >0.2, the percentage of time when the absorbance was >0.2 while upright, the percentage of time when the absorbance was >0.2 while supine, the number of episodes of the absorbance being >0.2, the number of episodes of the absorbance being >0.2 for more than 5 minutes, and the duration of the longest episode of absorbance ~0.2 16. Statistical analysis Data were expressed as median and range. The Kruskal-Wallis non-parametric test was used to assess statistical significance. If statistical significance was achieved (p
Demographic and symptom score data Patients with SIM in the distal oesophagus or OGJ were older than those without; their median age was 55 years (range: 3 l-72) as compared with 47.5 (24-72) for GERD patients without IM (~~0.05). There was no difference between the LSBO, SSBO and USSBO groups. Patients with SIM in the distal oesophagus, regardless of its length, were predominantly males, i.e., 32 males and 2 females vs 20 males and 12 females in the GERD group (~~0.01). The smoking and drinking habits of patients, and their use of medication are summarised in Table I. 253
Acid/bile reflux and intestinal metaplasia
Table 1. Demographics
and symptom
9ERD In=921
UB9B9 In=91
23.0 (21-251
47.5 (24-721
(31-681
C315:71
Sex M:F
50 (355-6721
9:o
8:O
15:2
9
15
3
1
9
12
32
9
7
14
Al
A4
A4
K 02
i: 01
Ko 01
lf81
4; ('l-81
[:81
[i-81
IO!31
12.5" (4-231
7.0 (3-I 81
10.0" (3-201
&31
-
24" (2-I 801
12 IO-1 201
24^ [O-I 801
60 (4-2401
Use of medication
i: Cl5 D8 *
Heartburn score
Duration of symptoms
LOB0 In=171
20:12
Alcohol intake ~50 g/day
score
SSBO In=91
57
Smoking Cl 0 cigarettes/day
Overall symptom
data.
In=121
cantds
Age
score
in months
*,n
'
’ ~~0.05 vs control subjects; n ~~0.05 vs USSBO patients. expressed as median and range lin brackets]. Abbreviations:
Table II. Manometric
data
Resultes are see list.
ILESI.
In=121
GERD k321
Resting pressure in mmHg
16.5 (7-331
12" (2-351
I:-:61
Abdominal length in mm
28.5 (13-351
25" (8-691
32 [l&441
23.5" (19-391
16^"§ (5-421
Total length in mm
42.5 (28-471
42.5" (21-791
50 (25-601
36" (30-521
32"'§ (14-521
cenlrals
II9990
s999
In=91
In=91
LS99 he171
IO (6-I 81
6.5"*" (4-201
'
* ~~0.05 vs control subjects; ’ ~~0.05 vs SSBOAJSSBO patients; § pcO.05 vs GERO patients. Results are expressed as median and range Il. Abbreviations: see list.
lble III. Intestinal
Manometric data The median LES resting pressure in the patients was lower than in controls. LSBO patients had the lowest LES resting pressure. No difference was observed between SSBO or USSBO and GERD as regards LES manometric characteristics (Table II). LES was defective in 8 out of 17 (47%) LSBO, 1 out of 8 (13%) SSBO, none of 9 USSBO, and 5 out of 32 (16%) GERD patients. The amplitude of the oesophageal contractions was significantly lower in LSBO (median 53.5 mmHg, range: 27-l 12) than in the control group (median 83 mmHg, range: 45-171) (p
metaplasia.
We
I
II
III
LSBO SSBO
2 0
5
8
USSBO Total
3
1 1
4 1
5
7
13
* In 4 cases I2 LISSBO and 2 SSBO patients1 tinguish the type of intestinal metaplasia.
254
The main symptoms were heartburn (40/66: 70%), belching (31/66: 47%), and retrosternal pain (30/66: 45%). In 26 out of 66 patients (40%), the symptoms were severe enough to interfere with daily activities, work or social life (symptom score >14). There was no difference in the overall symptom scores for the four groups of patients; LSBO patients had a higher score for heartburn (~~0.05) than the other groups, however, and a longer history of symptoms (Table I).
it was impossible
-
TabIs IY H. py/ori
H. pylori+ infection
infection.
GE66 hl=321
6B666 tdl
7132 [22%1
219
O/8
4/17
[22%1
[O%l
(23%)
to disAbbreviations:
see list.
6666 k61
C. Zaninotto et al.
Table
U. Twenty-four hour pH monitoring data
2% = s:, 99999 l9no In=91
Total time pH <4
z
In=l7~
0.1 4.5'" 1.7" 5" 12.8*""" KLO-1.51 fO.l-37.51 fO.l-4.71 fO.5-14.31 [I .5-66.11
Upright time 0.2 4.3"" 2.4" pH <4 (0.0-2.31 [0.2-41.21 [0.2-7.31
2.4" (0.4-5.81
8.8*05" (0.9-801
Supine time pH <4
0.0 (0.0-0.81
2.6' (O-311
0.6 (0.0~5.61
6.7' 13.3'""" [O-30.81 f2.3-49.31
Totaln. acid episodes
3.5 co-21I
25""" H-2831
16" 12-341
23* (g-341
72~s~ [20-2001
Acid refluxes lasting more than 5 min
0.0 CO-01
3’” (O-201
1.o* (O-51
3.5" (O-71
1OGO§ CO-261
Longest acid reflux episode fminl
1.0 (O-51
14@ II-1451
6.0* U-361
16.5' (1-1111
(3-1871
28”“§”
* p
Acid exposure in the distal oesophagus Patients with IM in the distal oesophagus had a greater exposure to acid gastric contents than controls. However, patients with LSBO had a longer exposure time at pH ~4 than all the other groups. The results for acid exposure are shown in Table V. On a single-patient basis, a positive 24-hour pH monitoring test result was found in 78% of patients with GERD, 30% of patients with USSBO, 75% of patients with SSBO and 94% of patients with LSBO. Bile exposure in distal oesophagus Exposure to bile in the distal oesophagus was significantly greater in the LSBO patients than in any of the other groups, while no difference was observed between GERD, SSBO and USSBO patients, or between SSBO and USSBO patients and controls (Fig. 1). Results of the logistic regression test are shown in Table VI. The presence of bile, a low resting pressure of the LES, age and sex were the variables that entered the model and predicted the presence of LSBO with a probability of 83%.
Odds retio
0
:
*
0
T
al
Confidence
&nits
Total bile exposure LES resting pressure
The probability of developing increasingly lengthy IM in the distal oesophagus (USSBO, SSBO or LSBO) rose by 10% for each 3% increment in total bile exposure, by 36% for a 3 mmHg reduction in LES resting pressure and by 33% for an additional 10 years of age. Male sex was associated with a 48 times greater risk of developing IM.
Discussion Controls
GERD
USSBO
SSBO
LSBO*
Fip. X24-hour bile exposure in distal oesophagus in patients with long segment Barrett’s oesophagus ILSBOI, short segment Barrett’s oesophagus [SSBOI , ultra-short segment Barrett’s oesophagus MiSBOI , gastro-oesophageal reflux disease [GEROI and in controls [healthy volunteers). Patients with LSBO have longer exposure to bile in their distal oesophagus than all other groups. *p
The results of this study confirm that the extensive replacement of the squamous epithelium of the distal oesophagus with intestinal-type “goblet” cells (specialised intestinal metaplasia), i.e., the so-called LSBO, is the direct consequence of long-standing, severe GERD. The patients affected are older than patients with uncomplicated GERD, they have higher scores for heartburn (the most typical symptom of GERD), and
Acid/bile reflun and intestinal metaplasia
median duration of their symptoms was of 5 years, i.e., twice as long as in patients with uncomplicated GERD. The LES of these patients is scarcely competent, mainly because of a low resting pressure and a short abdominal segment; a defective LES is found three times more often in LSBO than in GERD patients. Due to this LES incompetence, patients with LSBO are more prone to their distal oesophagus being exposed to acid gastric juices for longer periods, especially at night, when the patient lies down and the protective effect of gravity is absent. Although a clear difference in oesophageal motility between the four patient groups was not demonstrated, a lower amplitude of oesophageal contractions was observed in LSBO patients than in controls (however, our controls were also younger than the patients). LSBO patients also had longer single episodes of acid reflux and more reflux episodes lasting more than 5 minutes than the other patient groups, confirming that their oesophageal clearance had deteriorated Is. However, oesop h ag eal acid exposure alone is not sufficient to explain why long segments of IM develop only in certain patients with severe GERD and several aspects of the pathogenesis of Barrett’s oesophagus are still not clear. Two key questions remain to be answered. First, what are the relationships between LSBO, SSBO and USSBO? Second, which noxious agent(s) can induce the progressive intestinalisation of the oesophageal epithelium? Some Authors claim that USSBO should be considered as a totally different disease from true Barrett’s oesophagus and they have reported no association with erosive oesophagitis, but a positive association with H. pylori infection and with mucosal atrophy and metaplasia in other segments of the stomach 19. It was, therefore, argued that USSBO should be considered as an extension of gastritis rather than as a part of reflux disease. Further evidence, in favour of this theory, lies in the observation that patients with LSBO, SSBO and USSBO are of comparable median age, both in the present study and in others 20, thus suggesting a different mechanism. After careful physiological studies, DeMeester and DeMeester 2o have hypothesised a totally different pathogenesis. The so-called two-step theory has been formulated, according to which all LSBO derive from SSBO or USSBO. The first step consists in the creeping replacement of the cardiac mucosa with intestinal-type cells. The cardia region is the furthest away from the stomach and it is the area most likely to be exposed to a pH of 3 to 5 due to the dilution and neutralisation of refluxed acid by the saliva: the exposure of columnar epithelial cells to a pH of 3 to 5 has been shown to encourage the development of IM 21. This process also induces inflammatory changes in the muscular-is propria of the LES and leads to a progressive deterioration in the intrinsic tone of the LES; this will ultimately lead to a 256
greater quantity of gastric contents penetrating the distal oesophagus and further damaging the oesophageal mucosa, eventually causing extensive substitution by specialised IM (second step). This theory has been supported by Loughney et al. 21, who demonstrated a greater acid exposure in patients with SSBO by monitoring the pH 5 cm above the LES; these patients also revealed an increased acid exposure at LES level, though this was not statistically significant compared to normal subjects. The “two-step” theory is supported only in part by data emerging from in this study: patients with LSBO were not older, but they did have a longer history of symptomatic reflux disease than all the other groups; all three groups with intestinal-type metaplasia (LSBO; SSBO and USSBO) had a greater acid exposure in the distal oesophagus than healthy controls and the total acid exposure time increased progressively from USSBO to LSBO. It might be argued that the healthy subjects, in the present study, probably had a very low acid exposure because of their younger age. Acid exposure is generally little affected by age, however 2223, and the low exposure of the healthy control group in this study is probably due to the liquid diet administered during bile and pH monitoring, with ingredients that do not interfere with bile absorbance - a diet that can hardly be considered as physiological and that probably reduces the physiological number of reflux episodes and their duration. Given that patients were fed the same diet as controls, the different results obtained were considered reliable. However, when examining data on a single-patient basis, the majority of patients with USSBO did not have abnormal acid exposure in their distal oesophagus and the development of focal islands of intestinal metaplasia cannot be explained by abnormal acid exposure alone. Indeed, a more distinct correlation is observed between abnormal 24-hour pH monitoring, SSBO and LSBO: it seems more likely that these two abnormalities are both related to excessive acid exposure in the distal oesophagus and SSBO (but not USSBO) is probably the precursor of LSBO. Why do long segments of intestinal metaplasia only develop in a minority of patients with GERD? Does bile play a part in this process? The results of the present study provide further evidence of the involvement of bile: the proportion of time with exposure to bile was more than 4 times higher in patients with LSBO than in those with GERD. During the night, while patients are supine, the distal oesophagus with LSBO is bathed in bile for nearly 20% of the time. Moreover, the presence of long segments of IM was predicted with an 83% probability by four variables used in a model constructed with the logistic regression test, i.e. the presence of bile, LES resting pressure, age and sex. However, this study cannot rule out the possibility that bile is merely secondary to excessive acid exposure (the more the gastric contents flow back into the gullet,
C. Zaninotto et al.
the easier it is to detect bile), but some interesting experimental trials have shown that bile is directly capable of differentiating cell cultures towards IM 24. In any case, bile is feasibly not the only cause of the onset of LSBO: genetic factors linked to the white race and the male sex, and smoking and drinking habits are probably also implicated. No clear interpretation linking different types of IM to different extensions of Barrett’s oesophagus or different types of reflux (acid or acid plus bile) has been found as yet and this aspect of the disease needs further investigation. Longitudinal studies are also required to confirm the hypothesis that SSBO is the precursor of LSBO. The results of this study would also suggest some therapeutic implications: LSBO patients have the most severe GERD and it has been demonstrated that acid reflux persists in most of these patients despite adequate symptom control with appropriate antisecretory drugs 25. Such medication also fails to prevent bile reflux so, with medication alone, the two causes of LSBO (acid and bile reflux in the distal oesophagus) will persist and the disease will more than likely progress. The surgical option of fundoplication should consequently be considered in these patients. List of abbreviations In Tables: Controls: healthy volunteers: A: antiacids; B: histamine 2-receptor antagonists; C: proton pump inhibitors: D: prokinetics. GERD: gastro-oesophageal reflux disease; H. py/ori: Helicobacter py/ori; HID: high iron diamine; HV: healthy volunteers; IM: intestinal metaplasia; LES: lower oesophageal sphincter; LSBO: Long Segment Barrett’s Oesophagus; OGJ: oesophago-gastric junction PAS: periodic acid-Schiff; SIM: specialised intestinal metaplasia; SSBO: Short Segment Barrett’s Oesophagus; LISSBO: Ultra-Short Barrett’s Oesophagus.
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1533-6.
7 Ruol A, Parenti AR, Zaninotto G, Merigliano S, Costantini M, et al. Intestinal metaplasia is the probable common precursor of
adenocarcinoma in Barrett’s esophagus and adenocarcinoma of the gastric cardia. Cancer 2000;88:2520-8. 8 Provenzale D, Kemp JA, Arora S, Wong JB. A guide for surveillance of patients with Barrett’s esophagus. Am J Gastroenterol 1994;89:670-80. y Oberg S, DeMeester TR, Peters JH, Hagen JA, Nigro JJ, De Meester S, et al. The extent of Barrett’s esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure. J Thorac Cardiovasc Surg 1999; 117:572-82. lo Savary M, Miller G. L’oesophage. Manuel et atlas d’endoscopie. Solothurn: Gassmann; 1977. ‘I Zaninotto G, and the G.I.S.U. Prevalence of intestinal metaplasia in the distal oesophagus, oesophagogastric junction and gastric cardia in symptomatic patients in North-East Italy: a prospective, descriptive survey. Digest Liver Dis 200 1;33:3 16-2 1. Iz Fireman Z, Wagner G, Weissman J, Kopelman Y, Wagner Y, Groissman G, et al. Prevalence of short-segment Barrett’s epithehum. Digest Liver Dis 2001;33:322-5. I3 Filipe Ml, Munoz N, Matko I, Kato I, Pompe-Kirn V, Juterserk A, et al. Intestinal metaplasia types and the risk of gastric cancer: a cohort study in Slovenia. lnt J Cancer 1994;57:324-9. I4 Passaretti S, Zaninotto G, Di Martin0 N, Leo P, Costantini M, Baldi F. Standards for oesophageal manometry. A position statement from the Gruppo Italian0 di Studio Motilita Apparato Digerente (GISMAD) Digest Liver Dis 2000;32:46-55. Is Jamieson JR, Stein HJ, DeMeester TR, Bonavina L, Schwizer W, Hinder RA, et al. Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity and reproducibility. Am J Gastroenterol 199287: 104- 11. Ih Kauer WK, Peters JH, DeMeester TR, Ireland AP, Bremner CG, Hagen JA. Mixed reflux of gastric and duodenal juices is more harmful to the esophagus than gastric juice alone. The need for surgical therapy re-emphasized. Ann Surg 1995;222:525-33. ” Hosmer DW Lemeshow S. Applied logistic regression. New York: Wiley;‘1989. ” Zaninotto G, DeMeester TR, Bremner CG, Smirk TC, Cheng SC. Esophageal function in patients with reflux induced stricture and its relevance to surgical treatment. Ann Thorac Surg 1989;47:362-70. ” El-Serag HB, Sonnenberg A, Jamal MM, Kunkel D, Crooks L, Feddersen RM. Characteristics of intestinal metaplasia in the gastric cardia. Am J Gastroenterol 1999;94:622-7. ” DeMeester SR, DeMeester TR. Columnar mucosa and intestinal metaplasia of the esophagus. Fifty years of controversy. Ann Surg 2000;3:303-21. ” Loughney T, Maydonovitch CL, Wong RKH. Esophageal manometry and ambulatory 24-hour pH monitoring in patients with short and long segment Barrett’s esophagus. Am J Gastroenterol 1998;93:916-9. 2? Richter JE, Bradley LA, De Meester TR, Wu WC. Normal 24-hr ambulatory esophageal pH values. Influence of study center, pH electrode, age and gender. Dig Dis Sci 1992;37:849-56. ” Ortiz A, Martinez de Haro LF, Parrilla P, Molina J, Bermejo J, Munitz V. 24-h pH monitoring is necessary to assess acid reflux suppression in patients with Barrett’s oesophagus undergoing treatment with proton pump inhibitors. Br J Surg 1999;86: 1472-4. I4 Ransford RAJ, Jankowsky JAZ. Genetic versus environmental interactions in the esophagitis-metaplasia-dysplasia-adenocarcinoma sequence (MCS) of Barrett’s esophagus. Acta Gastroenterol Belg 2000;63: 18-21. *’ Stein HJ, Kauer WKH, Feussner H, Siewert JR. Bile reflux in benign and malignant Barrett’s esophagus: effect of medical acid suppression and Nissen fundoplication J Gastrointest Surg 1998;2:333-41.
257