In gastroesophageal reflux disease, is the decrease in lower esophageal sphincter tone possibly secondary to acid reflux?
D. Liebermann-Meffert (Munich)
It is well known that refluxed gastric contents injure the mucosa of the esophagus, the longer they stay there. In a vicious circle this seems to result in what is called gastroesophageal reflux disease (GERD). The responsible causality, however, the sequence of the events and the respective principle mechanisms remain still matter of debate [1-7]. Besides, wide methodological differences and inhomogenity of the study designs render comparisons between the various reports impossible.
In order to grade and judge one of the tangible components of the complex aspects, we have assessed the effect of repeated, prolonged experimental intraluminal acidifications on the motor activity of the body of the esophagus and the high pressure zone of the lower esophageal sphincter (LEHPZ) under controlled and standardized conditions.
A total of fifty-one female cats obtained from an industry breeding animal unit, specific pathogen free (SPF), one year old, weighing 2,5-3,2 kg, were examined.
Ketamine hydrochloride i.v. was used to anesthetize the animals after 12 hours fasting. A thermistor coupler attached to an endotracheal tube registered respiration. The cats were placed in supine position on a board, the LEHPZ was identified manometrically and fluids of different pH concentrations were infused 5 times at 2 day intervals into the esophageal body through a tube ending 6 cm proximal to the zone of greatest LES pressure. Infused were 0,1 N HC1 solutions of pH 1 (17 cats), pH 2 (7 cats), pH 3,8 (7 cats), and tube water of ca. pH 7 (20 cats) at rates of 1 ml/min for consecutive periods of 45 min each. The volumes were identical.
We recorded the pressures throughout the LES and esophagus before the first, the third, the fifth fluid applications and 6 and 12 weeks later by stepwise pull through (20 mm/20 s) and steady (60 min) water perfusion manometry techniques using a 6 lumen device with side holes 5 mm apart. A conventional Synectics monitoring system and in addition a computer recording program designed by our group [8, 9] was used. At the same sessions endoscopy and biopsy with subsequent histology were performed. Clearance was monitored after a 5 ml 0,1 N HC1 pH 1 bolus instillation, respectively. All values were compared with the initial control data.
Lasting acid exposure below pH 4 caused all kind of motor disorders of the tubular esophagus, of the LES and produced esophagitis. Intraesophageal acidification abruptly produced perfusion related hypercontractions for 20 to 100 mmHg (Figure 1), which during the irrigating period gradually returned to preperfusion values. When compared with the preperfusion recordings (Figure 2) the motor disorders referred to long term pressure decrease in both LES and esophageal contraction, incomplete LES relaxations, untidy peristaltic pattern (Figures 3, 4 and 5), such as increase in the frequency of deglutition
(p < 0,01), decrease in the propagating velocity of the primary peristaltic contractions
(p < 0,05) and the occurrence of multipeaked waves (Figure 3) and delayed clearance.
The motor disorders developed prior to esophagitis, both strongly correlating with the pH values; the lower the pH, the greater was the damage to function (Figures 6 and 7) and mucosa. Long term pH 1 exposure was a disaster leading to severe esophagitis erosions, stenosis and fatal stricture which was lethal in one third of our cats. Less severe LES disorders and mucosal injuries turned more or less towards normal values after acid relief within three months after the end of exposure, but not the motility pattern of the esophagus and its clearance. Spastic contractions of the tubular esophagus and delayed clearance remained a common finding after acid irrigation with low pH.
Figure 1. Example of the effect of water (a) followed by acid perfusion of pH 1 (b) on the behaviour of the pressure in the LES. Acid clearly elicited increased pressure and contraction frequence. Computerized data.
Figure 2. Example of a manometric tracing of the lower esophageal high pressure zone (LEHPZ) and esophageal contractions (SW) before the first acid irrigation in cat K 20. Relaxation of the LES starts usually before the peak of the SW occurs. RRP = respiratory reversal point.
Figure 3. Example of a manometric tracing of the impaired LEHPZ with low LES pressure, incomplete and delayed relaxations as response to the multipeaked, prolonged and low esophageal contraction (SW). Record 5 days after the first and before the third acid irrigation in cat K 20.
Figure 4. Diagram
showing the changes in the LEHPZ developing after repeated intraesophageal acid perfusion pH 1. Mean values of 17 cats.
The findings reported here correlated with those previously published by us elsewhere [6-9] and equal those of other studies [1, 3, 4] that long term intraesophageal acid perfusion produces experimental esophagitis in the cat, significant in vivo decrease of resting LES pressure and motor disturbances of the tubular esophagus. This suggests that the esophagus is pH sensitive and does not support the concept that the principal stimulus for esophageal clearance under reflux conditions is the intraluminal distention . The findings, however, are consistent with the idea that hypersensitivity to acid is an important underlying pathological feature of this syndrome [2-4] including biochemical alterations in the cellular metabolism . This model also provides evidence that acid injury that may prevail under the conditions of acid gastric reflux exerts an even stronger noxious effect on the motility of the esophagus than on the LES and the mucosa.
Figure 5. Diagram showing the changes in the tubular esophagus developing after repeated intraesophageal acid perfusion pH 1. Mean values of 17 cats.
Figure 6. Completeness of LES relaxations at time of the fifth, last perfusion with acid pH 1.
Figure 7. Changes of esophageal contractions two weeks (left column) and eight weeks (right colunm) after acid irrigation.
2. Biancani P, Billett G, Hillemeier C, Nissensohn N, Rhim BY, Szewczak S, Behar J. Acute experimental esophagitis impairs signal transduction in cat lower esophageal sphincter circular muscle. Gastroenterology 1992;103:1199-1206.
6. Liebermann-Meffert D, Klaus D, Vosmeer S, Allgöwer M. Effect of intraesophageal bile and acid (HCl) perfusion on the action of the lower esophageal sphincter. Scand J Gastroenterol 1984;19:237-241.
8. Eckardt JM. Computerunterstützte Datenerfassung und -auswertung bei der Perfusionsmanometrie des unteren Ösophagussphinkters, gezeigt anhand einer pharmakologischen Studie bei Katzen (mit D. Liebermann-Meffert). Dissertation Basel, 1990.
9. Egloff JP. Computergestützte Analyse der Wirkung des Antacidums Maalox 70 auf die Motorik und Peristaltik des unteren Ösophagussphinkters im Vergleich mit Placebo und Säure. Eine experimentelle Studie (mit D. Liebermann-Meffert). Dissertation Basel, 1992.