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Chronic xerostomia increases esophageal acid exposure and is associated with esophageal injury
Chronic Xerostomia Increases Esophageal Acid Exposure and Is Associated with Esophageal Injury MARKA. KORSTEN,M.D., ALAN S. ROSMAN,M.D., SUSANFISHBEIN,M.D., ROBERTD. SHLEIN, M.D., HEIDI E. GOLDBERG,M.D., ALEXANDERBIENER,M.D., Bronx, New York, and New York, New York
OBJECTIVE: To assess the effects of chronic xerostomia on parameters of gastroesophageal reflux and esophagitis. DESIGN: Observational study of a cohort of male patients with xerostomia and age-matched control subjects. SE!I+T.ING:Tertiary-care Veterans Affairs Medical Center. SUBJECTS: Sixteen male patients with chronic xerostomia secondary to radiation for head and neck cancers or medications. Nineteen agematched male control subjects with comparable alcohol and smoking histories. MEASUREMENTSANDMAINRESULTS: Esophageal motility was similar in patients with xerostomia and controls. Clearance of acid from the esophagus and 24-hour intraesophageal pH were markedly abnormal in patients with xerostomia. Symptoms and signs of esophagitis were significantly more frequent in subjects with xerostomia. CONCLUSIONS: Chronic xerostomia may predispose to esophageal injury, at least in part, by decreasing the clearance of acid from the esophagus and altering 24-hour intraesophageal pH. Esophageal injury is a previously unreported complication of long-term salivary deficiency.
From the Gastrointestinal Section, Veterans Affairs Medical Center (MAK, ASR, SF, RDS, HEG, AB). Bronx, New York, and Mount Sinar School of Medicine (MAK, ASR. SF, RDS. HEG, AB), New York, New York. This work was supported in part by a grant from the Department of Veterans Affairs. Requests for reprints should be addressed to Mark A. Korsten, M.D.. Alcohol Research Center, Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York 10468. Current addresses: Dr. Alan S. Rosman, Veterans Affairs Medical Center. 130 West Kingsbridge Road, Bronx, New York 10468: Dr. Susan Fishbein, 1865 Amsterdam Avenue, New York, New York 10031; Dr. Robert D. Shlein, 1777 Hamburg Turnpike, Wayne, New Jersey 07420; Dr. Heidi E. Goldberg, 5651 49th Street North, St. Petersburg, Florida 33709; Dr. Alexander Biener. 466 Old Hook Road #12, Emerson, New Jersey 07630. Manuscript submitted March 15, 1990, and accepted in revised form February 19. 1991.
number of factors protect the esophagus from acid-mediated injury. Among these, acid clearance from the esophagus appears to play a central role. Acid is cleared from the esophagus by a twostep process involving peristalsis and acid neutralization by saliva. The importance of saliva in the neutralization of residual acid in the esophagus has been demonstrated under experimental conditions [l-3]. Esophageal acid clearance is clearly delayed in such studies when saliva production is inhibited (by atropine) or when saliva delivery into the esophagus is abolished by aspiration. However, the clinical significance of prolonged salivary deficiency is not known. To study this issue, we assessed a number of esophageal parameters in a group of patients with chronic xerostomia. We found that patients with xerostomia had delayed esophageal acid clearance and abnormal 24-hour esophageal pH and were likely to have histologic and clinical evidence of esophagitis.
A
PATIENTS AND METHODS Patients A total of 16 male patients (mean age 58.6 years) with xerostomia were consecutively referred for clinical investigation. Xerostomia had been present for at least 2 years in all patients. In 12 of 16 patients, xerostomia was attributable to surgical and radiotherapeutic treatment of head and neck cancers. In the remainder, xerostomia was secondary to medications used to treat psychiatric problems or hypertension. Haloperidol (3.0 mg three times daily) was being administered to two subjects. One patient each was receiving lithium (600 mg three times daily) and clonidine 1.2 mg/day. In the cancer patients, the radiotherapy ports included the salivary glands but did not include the middle and distal esophagus. Eight of the 16 patients admitted to a past history of alcohol abuse, three were social drinkers, and five were abstainers. Twelve of the 16 patients were heavy smokers and two were nonsmokers. Smoking data were not available for the remaining two patients. Nineteen age-matched male subjects without xerostomia and without persistent or severe symptoms of reflux served as controls; 10 of these asymptomatic subjects underwent 24-hour intraesophageal pH monitoring. The smoking and drinking histories in these control patients were similar to those in the subjects with xerostomJune
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ia. Ten of these subjects had a history of alcoholism (consuming more than 150 g/day), three were abstainers, and six were social drinkers. Fourteen of the control subjects smoked heavily (two or more packs per day), three smoked occasionally, and one was a nonsmoker. Antacids and Hz-receptor antagonists were discontinued in all subjects 1 week prior to all investigations. Informed consent was obtained from each subject. The study was approved by the Human Studies Subcommittee of the Bronx Veterans Administration Medical Center. Sialometry Mixed saliva was obtained as previously described [4]. Subjects were instructed to expectorate into a graduated cylinder for a period of 20 minutes. Immediately following this, they were given a 1 cm3 piece of paraffin wax and instructed to chew it after allowing it to soften in the mouth [4]. Saliva was collected again into a graduated cylinder covered by a gauze sponge. Total collection time for this stimulated sample was 4 minutes. Esophageal Manometry Motility studies were performed in the left lateral decubitus position using a 6-lumen polyvinyl catheter (ES42R, Arndorfer Medical Specialties Inc., Greendale, Wisconsin). Each catheter had a 0.9mm internal diameter. The side holes of each catheter also had a 0.9 mm internal diameter. Four of the side holes were arranged radially around the distal tip of the catheter assembly, while two side holes were spaced at 5-cm intervals from the distal end. The catheters were connected to calibrated external pressure transducers (Hewlett-Packard 8870A, Palo Alto, California). The output from these transducers was transferred to a direct-writing recorder (Hewlett-Packard 7758A). Individual catheters were perfused at a rate of 0.5 ml/minute by a pneumohydraulic capillary infusion system (Arndorfer, Greendale, Wisconsin). Sensitivity of the system was greater than 300 mm Hg/second. Lower esophageal sphincter pressure (LESP) was determined by the rapid pull-through method and was taken as the average of six measurements from three radially oriented ports. Pressure recordings from the body of the esophagus were obtained relative to the LES using the same catheter assembly. The amplitude of esophageal contractions after three dry and three wet swallows (5 mL bolus of water) was determined 5 and 10 cm proximal to the LES. Esophageal Acid Clearance and Acid Reflux A pH probe (Beckman 39505, Beckman, Irvine, California) was positioned 5 cm above the previous-
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ly determined LESP [5]. A reference electrode (Beckman 40249) was affixed to the subject’s forearm and conduction was ensured by the use of electrode paste. With the subject in the left lateral decubitus position, a bolus of 15 mL of O.lN hydrochloric acid was instilled during a 30-second period through a port 5 cm proximal to the pH probe. Subjects were instructed to swallow at 30second intervals until the pH was greater than 5.0 or until the number of swallows reached 20. The pH in the lower esophagus was measured continuously using a Beckman 3500 digital pH meter and recorded on a Beckman strip chart recorder. After clearance of all acid from the distal esophagus, 300 mL of O.lN hydrochloric acid was instilled into the stomach with the probe remaining 5 cm above the LESP [6]. Various maneuvers to elicit reflux including Valsalva, abdominal pressure, and leg raising were performed. The presence of reflux was defined as a drop in pH in the distal esophagus during any of these manuevers. Twenty-Four-Hour pH Monitoring of the Esophagus The esophageal pH was monitored for 24 hours using a 1.8-mm flexible pH probe (MI-506, Microelectrodes, Inc., Londonderry, New Hampshire) placed 5 cm above the lower esophageal sphincter. Prior to insertion, the pH probe was calibrated to a pH of 4 and 7. The probe was connected to a Gastroreflux recorder (Model 706, Delmar Avionics, Irvine, California) and was evaluated using the Johnson-DeMeester system in which a composite score is derived by analyzing six components of the data: number of reflux episodes; number of reflux episodes greater than 5 minutes; duration of the longest reflux episode; the percentage of total time the esophageal pH is less than 4; and the percentage of time the esophageal pH is less than 4 in both the supine and recumbent positions [7]. A score of 0 to 20 was considered normal. Subjects were permitted to eat their usual diets during the 24-hour monitoring period. Esophagoscopy and Histology Endoscopy was performed using a standard Olympus OES upper gastrointestinal endoscope with the patient in the left lateral decubitus position. Endoscopic biopsies or cytologic material was obtained at least 5 cm proximal to the previously determined LESP and were evaluated by staff pathologists unaware of the subject’s history for the presence of inflammatory cells and keratinization. Assessment of keratinization was based on cytologic examination of exfoliated cells. The degree of orangeophilia in nucleated cells after Papanicolaou
ESOPHAGEAL
staining has been previously used as a measure of hyperkeratosis [8]. Subjects were questioned regarding the severity and frequency of substernal burning, water brash, and dysphagia.
6 ioo%
Figure 2. The number of reflux episodes during which esophageal pH fell below pH 4 (A) and the number of reflux episodes that exceeded 5 minutes in duration (6) in subjects with and without xerostomia (mean f SEM).
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CONTROLS
1. Esophageal acid clearance in subjects with and xerostomia. Fifteen milliliters of O.lN HCI was incm above the LESP, and subjects were instructed to at 30-second intervals until the pH was greater than the number of swallows exceeded 20.
with xerostomia and 98% in those without xerostomia, which was also a nonsignificant difference. Esophageal Acid Clearance and Acid Reflux The clearance of acid instilled into the esophagus was markedly delayed in subjects with xerostomia compared with control subjects (Figure 1). Ten of the 16 subjects with xerostomia failed to achieve a pH of 5 despite 20 swallows, four subjects required 18 swallows, and one needed 15 swallows. One patient with xerostomia was able to raise the intraesophageal pH to 5 after five swallows. In contrast, controls achieved the cutoff pH after a mean of five swallows (range: two to 12). This difference was highly significant (p
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RESULTS
Esophageal Manometry Mean LESP in control subjects (19.8 mm Hg) was not significantly different from that in subjects with xerostomia (21.7 mm Hg). Peristaltic amplitude after wet and dry swallows also did not differ significantly between control subjects and subjects with xerostomia. Ten centimeters proximal to the LES, the amplitude of contraction after dry swallows was 41.6 mm Hg in patients with xerostomia and 39.4 mm Hg in control subjects. After wet swallows, the mean amplitude was 45.5 mm Hg in subjects with xerostomia and 46.7 mm Hg in controls at this same location. Five centimeters proximal to the LES, there were also no differences between subjects with and without xerostomia after either dry (40.6 mm Hg versus 52.2 mm Hg, respectively) or wet (46.2 mm Hg versus 55.6 mm Hg, respectively) swallows. In addition, the number of nonperistaltic simultaneous contractions following swallows was similar in subjects with (5% of swallows) and without xerostomia (2%). The percentage of swallows followed by peristaltic activity was 93% in subjects
OF CHRONIC
>20
Statistical Analysis The significance of differences between subjects with and without xerostomia was evaluated by Student’s t-test (parametric data) and Mann-Whitney U or chi-square tests (nonparametric data). Arcsine transformation was used on percentage data.
Salivary Flow Mean salivary flow in control subjects was 0.58 ml/minute in the basal state and 3.4 ml/minute after stimulation with paraffin wax. Basal flow rate was less than 0.1 ml/minute and stimulated flow less than 0.8 ml/minute in all subjects with xerostomia.
EFFECTS
Controls
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Subjects with Xerostomia
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Subjects wjth Xerostomla
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nents (the’difference between the two groups in terms of the percentage of time the pH was less than 4 in the supine position was no longer statistically significant).
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Twenty-Four-Hour pH Monitoring of the Esophagus The mean composite score was 54 in seven subjects with xerostomia and 4.2 in 10 control subjects (p <0.05, Mann-Whitney U test). Subjects with xerostomia had significant increases in the number of reflux episodes (Figure 2), the mean number of reflux episodes greater than 5 minutes (Figure 2), the mean duration of the longest reflux episode (Figure 3), and the percentage of time the pH was less than 4 in the supine and upright positions (Figure 4). Since subjects with xerostomia generally had more symptoms of gastroesophageal reflux than the control group employed, it is possible that controls in the study constituted an atypical subgroup of nonrefluxing veterans and that this factor led to the observed differences in 24-hour intraesophageal pH. This issue was addressed by reevaluating the pH data of a subgroup of subjects with xerostomia (five subjects) who were more comparable to the control group in terms of symptoms. Significant differences (p <0.05 or greater) persisted between subjects with and without xerostomia in terms of the composite score and in five of six of its compo-
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Esophagoscopy, Histology, and Symptomatology Esophagoscopy was performed in nine control subjects and all subjects with xerostomia. Endoscopic features of esophagitis (erythema and friability) were observed in four of the subjects with xerostomia, one of whom also had definite erosions. Signs of esophagitis were not observed in any of the controls. From the histologic standpoint, the frequency of hyperkeratosis was similar in controls and subjects with xerostomia. However, evidence of inflammation (histologic or cytologic presence of polymorphonuclear leukocytes) was significantly (p <0.05, chi-square contingency table analysis) more common in subjects with xerostomia (10 of 16) than in control subjects (two of nine). Of the 10 control subjects who underwent 24-hour pH monitoring, none complained of reflux symptoms. However, three control subjects who had an abnormal acid reflux test reported persistent substernal burning. This symptom was also uncommon among subjects with xerostomia prior to the development of salivary deficiency. After the onset of xerostomia, 11 subjects complained of substernal burning of a persistent (daily) or intermittent (several times per week) nature. There was microscopic evidence of inflammation in eight of the symptomatic subjects with xerostomia and in none of the three symptomatic control subjects.
COMMENTS Chronic xerostomia results in delayed acid clearance and abnormal 24-hour esophageal pH; these abnormalities of esophageal function were associated with esophageal inflammation. These changes
Upright
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Figure 4. The percentage of time esophageal pH was less than 4 in the supine and upright positions in subjects with and without xerostomia (mean f SEM).
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could not be attributed to alterations in esophageal motility, alcohol intake, or smoking habits. Although it has been previously shown that saliva plays a role in the normal physiology of the esophagus, the current study reports for the first time the deleterious effects of chronic salivary deficiency on the esophagus. The control subjects in this study were selected for their absence of persistent reflux symptoms and were, as a result, not completely comparable to the subjects with xerostomia. To address this concern, we evaluated the 24-hour pH scores of a subgroup of subjects with xerostomia who were relatively asymptomatic in terms of reflux and, therefore, more similar to the control group. Despite the exclusion of two patients with xerostomia who had severe reflux, significant differences persisted between the two groups. Had a more symptomatic control group been selected for study, it is likely that there would have have been more evidence of esophagitis and higher scores during 24-hour pH monitoring of the esophagus and, as a consequence, reduced differences noted relative to the group with xerostomia. In so doing, however, we would have obscured the fact that the cause of increased acid exposure in “normal” controls and subjects with xerostomia is quite distinct. Our findings indicate that in patients with xerostomia, increased acid exposure depends more on a severe impairment in esopbageal acid clearance than on gastroesophageal reflux per se. The likelihood of acid-mediated esophageal injury depends on the interplay of aggressive and defensive factors [9]. In patients lacking saliva, an important defensive component has been weakened, leading to defective neutralization of acid. The defensive potential of saliva is underscored by the data related to acid reflux. Reflux of acid following a 300-mL acid load was common in subjects with and without xerostomia, a finding consistent with previous studies demonstrating the lack of specificity of this test [lo]. Acid reflux was associated with abnormal 24-hour intraesophageal pH only in patients with xerostomia. The LESP constitutes an additional barrier to gastroesophageal reflux. However, we found that subjects with inadequate amounts of saliva had abnormal esophageal pH despite normal pressures in the LES zone. This is consistent with previous research demonstrating normal LESP values when esophagitis is mild [11,12]. Under this circumstance, acid reflux may occur during transient relaxations of the LES [13,14]. The current data suggest that such reflux may assume clinical importance in patients with xerostomia since they are incapable of neutralizing residual amounts of acid in the esophagus. As a consequence, the esoph-
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ageal mucosa of patients with xerostomia is exposed to acid for longer periods of time, which, presumably, increases the likelihood of injury. Histologic criteria for diagnosing esophagitis have been proposed based on specimens obtained by blind suction biopsy 1151. However, by standard clinical (i.e., endoscopic) techniques, a definitive pathologic diagnosis of esophagitis is difficult to attain. In this study, we attempted to establish the presence of esophagitis using directed endoscopic biopsy and brush cytology, but we recognize that these approaches lack both specificity and sensitivity [16-B]. Thus, although subjects with xerostomia displayed more markers of inflammation (i.e., histologic or cytologic presence of polymorphonuclear leukocytes) than asymptomatic controls, it would be premature to suggest a causal link between xerostomia, impaired acid clearance, and esophagitis. Dental caries, oral ulceration, and infections and gustatory dysfunction are well-known complications of xerostomia [19]. These alterations may lead to decreased food intake, speech impairment, and considerable discomfort. On the basis of the current study, impaired acid clearance and, possibly, esophageal injury should be added to this list of sequelae. This association may not have been previously appreciated given the tendency of patients to use nonprescription antacids and other remedies for acidrelated symptoms. Dysphagia was not noted by any of our patients with xerostomia. At present, therefore, we cannot predict whether the severity and/or duration of acid exposure in patients with xerostomia is sufficient to predispose to other complications of peptic esophagitis. Given that we observed relatively mild esophageal abnormalities after 2 or more years of xerostomia, strictures or other serious sequelae would seem to be unlikely prospects. On the basis of the current data, it appears reasonable to prevent acid production (Hz-receptor antagonists) or neutralize acid (antacids) in patients with xerostomia. Artificial saliva and sialagogues (especially, pilocarpine) [20] may also improve esophageal acid clearance. However, the relatively poor buffering capacity of artifical saliva (unpublished observations) may limit the usefulness of these substances in acid clearance. Fortunately, xerostomia is generally self-limited when due to irradiation or medications. Thus, the risk of esophageal injury should decline as spontaneous saliva production increases. An additional issue pertains to patients with preexisting gastroesophageal reflux who develop xerostomia. This subgroup of patients may require more intensive protective measures. The superimposition of salivary deficiency in these individuals could conceivably further increase the likelihood of esophageal dysfunction. June
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ACKNOWLEDGMENT We wish to thank Drs. Louis Loscalzo (Head and Neck Surgery) Lehrer (Radiation Therapy) for referring patients with xerostomia.
and therapy. Ann Intern Med 1982; 97: 93-103. 10. Ahtaridis G, Snape WJ, Cohen S. Lower esophageal sphincter pressure as an index of gastroesophageal acid reflux. Dig Dis Sci 1981; 26: 993-6. 11. Behar J, Sheahan DC. Histologic abnormalities in reflux esophagitis. Arch Pathol 1975; 99: 387-91. 12. Winans CS. Diagnostic evaluation of esophageal function. In: Proceedings of the Second International Symposium on the Esophagus and Gastroesophageal Junction, Ixtapa, Mexico, March 20-23. 1978: 25-30. 13. Dent J, Dodds WJ. Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980; 65: 25667. 14. Dodds WJ. Dent J, Hogan WJ, eta/. Mechanism of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982; 307: 1547-52. 15. Ismail-Beigi F, Horton PF, Pope CE II. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58: 163-74. 16. Fink SM. Barwick KW, Winchenbach CL, DeLuca V. McCallum RW. Reassessment of esophageal histology in normal subjects: a comparison of suction and endoscopic techniques. J Clin Gastroenterol 1983; 5: 177-83. 17. Knuff TE, Benjamin SB. Worshm GF, Hancock JE, Caste11 DO. Histologic evaluation of chronic gastroesophageal reflux. An evaluation of biopsy methods and diagnositc criteria. Dig Dis Sci 1984; 29: 194-201. 18.Zeitoun P. Pluot M, Vandromme L, Casola M. Evaluation by endoscopic biopsies of the histological criteria of reflux esophagitis. Gastroenterol Clin Biol 1987; 11: 6-11. 19. Streebny LM. Valdini A. Xerostomia: a neglected symptom. Arch Intern Med 1987; 147: 1333-7. 20. Greenspan D, Daniels TE. Effectiveness of pilocarpine in postradiation xerostomia. Cancer 1987; 59: 1123-5.
and Steven
REFERENCES 1. Helm JF, Dodds WJ, Hogan WJ. Soergel KH, Egide MS, Wood CM. Acid neutralizing capacity of human saliva. Gastroenterology 1982; 83: 69-74. 2. Helm JF, Dodds WJ, Riedel DR. Teeter BC, Hogan WJ. Arndorfer RC. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 1983; 85: 607-12. 3. Helm JF, Dodds WJ, Pelt LR, Palmer DW, Hogan WJ, Teeter BC. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984; 310: 284-8. 4. Silver LS. Worner TM, Korsten MA. Esophageal function in chronic alcoholics. Am J Gastroenterol 1986; 81: 423-7. 5. Booth DG, Kemmerer WI, Skinner DB. Acid clearing from the distal esophagus. Arch Surg 1968; 96: 731-4. 6. Kantrowitz PA, Corson JG, Fleishli DJ. Skinner DB. Measurement of gastroesophageal reflux. Gastroenterology 1968; 56: 666-73. 7. Johnson LF, DeMeester TR. Development of the 24hour intraesophageal pH monitoring composite scoring system. In: DeMeester TR, Skinner DB, eds. Esophageal disorders: pathophysiology and therapy. New York: Raven Press, 1985: 561-70. 8. Korsten MA, WornerTM, Feinman L, Shaw S, Federman Q. Balloon cytology in screening of asymptomatic alcoholics for esophageal cancer. Dig Dis Sci 1985; 30: 845-51. 9. Richter JB, Caste11 DO. Gastroesophageal reflux: pathogenesis, diagnosis,
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OBJECTIVE: To assess the effects of chronic xerostomia on parameters of gastroesophageal reflux and esophagitis. DESIGN: Observational study of a cohort of male patients with xerostomia and age-matched control subjects. SE!I+T.ING:Tertiary-care Veterans Affairs Medical Center. SUBJECTS: Sixteen male patients with chronic xerostomia secondary to radiation for head and neck cancers or medications. Nineteen agematched male control subjects with comparable alcohol and smoking histories. MEASUREMENTSANDMAINRESULTS: Esophageal motility was similar in patients with xerostomia and controls. Clearance of acid from the esophagus and 24-hour intraesophageal pH were markedly abnormal in patients with xerostomia. Symptoms and signs of esophagitis were significantly more frequent in subjects with xerostomia. CONCLUSIONS: Chronic xerostomia may predispose to esophageal injury, at least in part, by decreasing the clearance of acid from the esophagus and altering 24-hour intraesophageal pH. Esophageal injury is a previously unreported complication of long-term salivary deficiency.
From the Gastrointestinal Section, Veterans Affairs Medical Center (MAK, ASR, SF, RDS, HEG, AB). Bronx, New York, and Mount Sinar School of Medicine (MAK, ASR. SF, RDS. HEG, AB), New York, New York. This work was supported in part by a grant from the Department of Veterans Affairs. Requests for reprints should be addressed to Mark A. Korsten, M.D.. Alcohol Research Center, Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York 10468. Current addresses: Dr. Alan S. Rosman, Veterans Affairs Medical Center. 130 West Kingsbridge Road, Bronx, New York 10468: Dr. Susan Fishbein, 1865 Amsterdam Avenue, New York, New York 10031; Dr. Robert D. Shlein, 1777 Hamburg Turnpike, Wayne, New Jersey 07420; Dr. Heidi E. Goldberg, 5651 49th Street North, St. Petersburg, Florida 33709; Dr. Alexander Biener. 466 Old Hook Road #12, Emerson, New Jersey 07630. Manuscript submitted March 15, 1990, and accepted in revised form February 19. 1991.
number of factors protect the esophagus from acid-mediated injury. Among these, acid clearance from the esophagus appears to play a central role. Acid is cleared from the esophagus by a twostep process involving peristalsis and acid neutralization by saliva. The importance of saliva in the neutralization of residual acid in the esophagus has been demonstrated under experimental conditions [l-3]. Esophageal acid clearance is clearly delayed in such studies when saliva production is inhibited (by atropine) or when saliva delivery into the esophagus is abolished by aspiration. However, the clinical significance of prolonged salivary deficiency is not known. To study this issue, we assessed a number of esophageal parameters in a group of patients with chronic xerostomia. We found that patients with xerostomia had delayed esophageal acid clearance and abnormal 24-hour esophageal pH and were likely to have histologic and clinical evidence of esophagitis.
A
PATIENTS AND METHODS Patients A total of 16 male patients (mean age 58.6 years) with xerostomia were consecutively referred for clinical investigation. Xerostomia had been present for at least 2 years in all patients. In 12 of 16 patients, xerostomia was attributable to surgical and radiotherapeutic treatment of head and neck cancers. In the remainder, xerostomia was secondary to medications used to treat psychiatric problems or hypertension. Haloperidol (3.0 mg three times daily) was being administered to two subjects. One patient each was receiving lithium (600 mg three times daily) and clonidine 1.2 mg/day. In the cancer patients, the radiotherapy ports included the salivary glands but did not include the middle and distal esophagus. Eight of the 16 patients admitted to a past history of alcohol abuse, three were social drinkers, and five were abstainers. Twelve of the 16 patients were heavy smokers and two were nonsmokers. Smoking data were not available for the remaining two patients. Nineteen age-matched male subjects without xerostomia and without persistent or severe symptoms of reflux served as controls; 10 of these asymptomatic subjects underwent 24-hour intraesophageal pH monitoring. The smoking and drinking histories in these control patients were similar to those in the subjects with xerostomJune
1991
The American
Journal
of Medicine
Volume
90
701
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EFFECTS
OF CHRONIC
XEROSTOMIA
/ KORSTEN
ET AL
ia. Ten of these subjects had a history of alcoholism (consuming more than 150 g/day), three were abstainers, and six were social drinkers. Fourteen of the control subjects smoked heavily (two or more packs per day), three smoked occasionally, and one was a nonsmoker. Antacids and Hz-receptor antagonists were discontinued in all subjects 1 week prior to all investigations. Informed consent was obtained from each subject. The study was approved by the Human Studies Subcommittee of the Bronx Veterans Administration Medical Center. Sialometry Mixed saliva was obtained as previously described [4]. Subjects were instructed to expectorate into a graduated cylinder for a period of 20 minutes. Immediately following this, they were given a 1 cm3 piece of paraffin wax and instructed to chew it after allowing it to soften in the mouth [4]. Saliva was collected again into a graduated cylinder covered by a gauze sponge. Total collection time for this stimulated sample was 4 minutes. Esophageal Manometry Motility studies were performed in the left lateral decubitus position using a 6-lumen polyvinyl catheter (ES42R, Arndorfer Medical Specialties Inc., Greendale, Wisconsin). Each catheter had a 0.9mm internal diameter. The side holes of each catheter also had a 0.9 mm internal diameter. Four of the side holes were arranged radially around the distal tip of the catheter assembly, while two side holes were spaced at 5-cm intervals from the distal end. The catheters were connected to calibrated external pressure transducers (Hewlett-Packard 8870A, Palo Alto, California). The output from these transducers was transferred to a direct-writing recorder (Hewlett-Packard 7758A). Individual catheters were perfused at a rate of 0.5 ml/minute by a pneumohydraulic capillary infusion system (Arndorfer, Greendale, Wisconsin). Sensitivity of the system was greater than 300 mm Hg/second. Lower esophageal sphincter pressure (LESP) was determined by the rapid pull-through method and was taken as the average of six measurements from three radially oriented ports. Pressure recordings from the body of the esophagus were obtained relative to the LES using the same catheter assembly. The amplitude of esophageal contractions after three dry and three wet swallows (5 mL bolus of water) was determined 5 and 10 cm proximal to the LES. Esophageal Acid Clearance and Acid Reflux A pH probe (Beckman 39505, Beckman, Irvine, California) was positioned 5 cm above the previous-
702
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1991
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Journal
of Medicine
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ly determined LESP [5]. A reference electrode (Beckman 40249) was affixed to the subject’s forearm and conduction was ensured by the use of electrode paste. With the subject in the left lateral decubitus position, a bolus of 15 mL of O.lN hydrochloric acid was instilled during a 30-second period through a port 5 cm proximal to the pH probe. Subjects were instructed to swallow at 30second intervals until the pH was greater than 5.0 or until the number of swallows reached 20. The pH in the lower esophagus was measured continuously using a Beckman 3500 digital pH meter and recorded on a Beckman strip chart recorder. After clearance of all acid from the distal esophagus, 300 mL of O.lN hydrochloric acid was instilled into the stomach with the probe remaining 5 cm above the LESP [6]. Various maneuvers to elicit reflux including Valsalva, abdominal pressure, and leg raising were performed. The presence of reflux was defined as a drop in pH in the distal esophagus during any of these manuevers. Twenty-Four-Hour pH Monitoring of the Esophagus The esophageal pH was monitored for 24 hours using a 1.8-mm flexible pH probe (MI-506, Microelectrodes, Inc., Londonderry, New Hampshire) placed 5 cm above the lower esophageal sphincter. Prior to insertion, the pH probe was calibrated to a pH of 4 and 7. The probe was connected to a Gastroreflux recorder (Model 706, Delmar Avionics, Irvine, California) and was evaluated using the Johnson-DeMeester system in which a composite score is derived by analyzing six components of the data: number of reflux episodes; number of reflux episodes greater than 5 minutes; duration of the longest reflux episode; the percentage of total time the esophageal pH is less than 4; and the percentage of time the esophageal pH is less than 4 in both the supine and recumbent positions [7]. A score of 0 to 20 was considered normal. Subjects were permitted to eat their usual diets during the 24-hour monitoring period. Esophagoscopy and Histology Endoscopy was performed using a standard Olympus OES upper gastrointestinal endoscope with the patient in the left lateral decubitus position. Endoscopic biopsies or cytologic material was obtained at least 5 cm proximal to the previously determined LESP and were evaluated by staff pathologists unaware of the subject’s history for the presence of inflammatory cells and keratinization. Assessment of keratinization was based on cytologic examination of exfoliated cells. The degree of orangeophilia in nucleated cells after Papanicolaou
ESOPHAGEAL
staining has been previously used as a measure of hyperkeratosis [8]. Subjects were questioned regarding the severity and frequency of substernal burning, water brash, and dysphagia.
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Figure 2. The number of reflux episodes during which esophageal pH fell below pH 4 (A) and the number of reflux episodes that exceeded 5 minutes in duration (6) in subjects with and without xerostomia (mean f SEM).
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CONTROLS
1. Esophageal acid clearance in subjects with and xerostomia. Fifteen milliliters of O.lN HCI was incm above the LESP, and subjects were instructed to at 30-second intervals until the pH was greater than the number of swallows exceeded 20.
with xerostomia and 98% in those without xerostomia, which was also a nonsignificant difference. Esophageal Acid Clearance and Acid Reflux The clearance of acid instilled into the esophagus was markedly delayed in subjects with xerostomia compared with control subjects (Figure 1). Ten of the 16 subjects with xerostomia failed to achieve a pH of 5 despite 20 swallows, four subjects required 18 swallows, and one needed 15 swallows. One patient with xerostomia was able to raise the intraesophageal pH to 5 after five swallows. In contrast, controls achieved the cutoff pH after a mean of five swallows (range: two to 12). This difference was highly significant (p
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RESULTS
Esophageal Manometry Mean LESP in control subjects (19.8 mm Hg) was not significantly different from that in subjects with xerostomia (21.7 mm Hg). Peristaltic amplitude after wet and dry swallows also did not differ significantly between control subjects and subjects with xerostomia. Ten centimeters proximal to the LES, the amplitude of contraction after dry swallows was 41.6 mm Hg in patients with xerostomia and 39.4 mm Hg in control subjects. After wet swallows, the mean amplitude was 45.5 mm Hg in subjects with xerostomia and 46.7 mm Hg in controls at this same location. Five centimeters proximal to the LES, there were also no differences between subjects with and without xerostomia after either dry (40.6 mm Hg versus 52.2 mm Hg, respectively) or wet (46.2 mm Hg versus 55.6 mm Hg, respectively) swallows. In addition, the number of nonperistaltic simultaneous contractions following swallows was similar in subjects with (5% of swallows) and without xerostomia (2%). The percentage of swallows followed by peristaltic activity was 93% in subjects
OF CHRONIC
>20
Statistical Analysis The significance of differences between subjects with and without xerostomia was evaluated by Student’s t-test (parametric data) and Mann-Whitney U or chi-square tests (nonparametric data). Arcsine transformation was used on percentage data.
Salivary Flow Mean salivary flow in control subjects was 0.58 ml/minute in the basal state and 3.4 ml/minute after stimulation with paraffin wax. Basal flow rate was less than 0.1 ml/minute and stimulated flow less than 0.8 ml/minute in all subjects with xerostomia.
EFFECTS
Controls
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nents (the’difference between the two groups in terms of the percentage of time the pH was less than 4 in the supine position was no longer statistically significant).
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Twenty-Four-Hour pH Monitoring of the Esophagus The mean composite score was 54 in seven subjects with xerostomia and 4.2 in 10 control subjects (p <0.05, Mann-Whitney U test). Subjects with xerostomia had significant increases in the number of reflux episodes (Figure 2), the mean number of reflux episodes greater than 5 minutes (Figure 2), the mean duration of the longest reflux episode (Figure 3), and the percentage of time the pH was less than 4 in the supine and upright positions (Figure 4). Since subjects with xerostomia generally had more symptoms of gastroesophageal reflux than the control group employed, it is possible that controls in the study constituted an atypical subgroup of nonrefluxing veterans and that this factor led to the observed differences in 24-hour intraesophageal pH. This issue was addressed by reevaluating the pH data of a subgroup of subjects with xerostomia (five subjects) who were more comparable to the control group in terms of symptoms. Significant differences (p <0.05 or greater) persisted between subjects with and without xerostomia in terms of the composite score and in five of six of its compo-
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Esophagoscopy, Histology, and Symptomatology Esophagoscopy was performed in nine control subjects and all subjects with xerostomia. Endoscopic features of esophagitis (erythema and friability) were observed in four of the subjects with xerostomia, one of whom also had definite erosions. Signs of esophagitis were not observed in any of the controls. From the histologic standpoint, the frequency of hyperkeratosis was similar in controls and subjects with xerostomia. However, evidence of inflammation (histologic or cytologic presence of polymorphonuclear leukocytes) was significantly (p <0.05, chi-square contingency table analysis) more common in subjects with xerostomia (10 of 16) than in control subjects (two of nine). Of the 10 control subjects who underwent 24-hour pH monitoring, none complained of reflux symptoms. However, three control subjects who had an abnormal acid reflux test reported persistent substernal burning. This symptom was also uncommon among subjects with xerostomia prior to the development of salivary deficiency. After the onset of xerostomia, 11 subjects complained of substernal burning of a persistent (daily) or intermittent (several times per week) nature. There was microscopic evidence of inflammation in eight of the symptomatic subjects with xerostomia and in none of the three symptomatic control subjects.
COMMENTS Chronic xerostomia results in delayed acid clearance and abnormal 24-hour esophageal pH; these abnormalities of esophageal function were associated with esophageal inflammation. These changes
Upright
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Figure 4. The percentage of time esophageal pH was less than 4 in the supine and upright positions in subjects with and without xerostomia (mean f SEM).
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could not be attributed to alterations in esophageal motility, alcohol intake, or smoking habits. Although it has been previously shown that saliva plays a role in the normal physiology of the esophagus, the current study reports for the first time the deleterious effects of chronic salivary deficiency on the esophagus. The control subjects in this study were selected for their absence of persistent reflux symptoms and were, as a result, not completely comparable to the subjects with xerostomia. To address this concern, we evaluated the 24-hour pH scores of a subgroup of subjects with xerostomia who were relatively asymptomatic in terms of reflux and, therefore, more similar to the control group. Despite the exclusion of two patients with xerostomia who had severe reflux, significant differences persisted between the two groups. Had a more symptomatic control group been selected for study, it is likely that there would have have been more evidence of esophagitis and higher scores during 24-hour pH monitoring of the esophagus and, as a consequence, reduced differences noted relative to the group with xerostomia. In so doing, however, we would have obscured the fact that the cause of increased acid exposure in “normal” controls and subjects with xerostomia is quite distinct. Our findings indicate that in patients with xerostomia, increased acid exposure depends more on a severe impairment in esopbageal acid clearance than on gastroesophageal reflux per se. The likelihood of acid-mediated esophageal injury depends on the interplay of aggressive and defensive factors [9]. In patients lacking saliva, an important defensive component has been weakened, leading to defective neutralization of acid. The defensive potential of saliva is underscored by the data related to acid reflux. Reflux of acid following a 300-mL acid load was common in subjects with and without xerostomia, a finding consistent with previous studies demonstrating the lack of specificity of this test [lo]. Acid reflux was associated with abnormal 24-hour intraesophageal pH only in patients with xerostomia. The LESP constitutes an additional barrier to gastroesophageal reflux. However, we found that subjects with inadequate amounts of saliva had abnormal esophageal pH despite normal pressures in the LES zone. This is consistent with previous research demonstrating normal LESP values when esophagitis is mild [11,12]. Under this circumstance, acid reflux may occur during transient relaxations of the LES [13,14]. The current data suggest that such reflux may assume clinical importance in patients with xerostomia since they are incapable of neutralizing residual amounts of acid in the esophagus. As a consequence, the esoph-
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ageal mucosa of patients with xerostomia is exposed to acid for longer periods of time, which, presumably, increases the likelihood of injury. Histologic criteria for diagnosing esophagitis have been proposed based on specimens obtained by blind suction biopsy 1151. However, by standard clinical (i.e., endoscopic) techniques, a definitive pathologic diagnosis of esophagitis is difficult to attain. In this study, we attempted to establish the presence of esophagitis using directed endoscopic biopsy and brush cytology, but we recognize that these approaches lack both specificity and sensitivity [16-B]. Thus, although subjects with xerostomia displayed more markers of inflammation (i.e., histologic or cytologic presence of polymorphonuclear leukocytes) than asymptomatic controls, it would be premature to suggest a causal link between xerostomia, impaired acid clearance, and esophagitis. Dental caries, oral ulceration, and infections and gustatory dysfunction are well-known complications of xerostomia [19]. These alterations may lead to decreased food intake, speech impairment, and considerable discomfort. On the basis of the current study, impaired acid clearance and, possibly, esophageal injury should be added to this list of sequelae. This association may not have been previously appreciated given the tendency of patients to use nonprescription antacids and other remedies for acidrelated symptoms. Dysphagia was not noted by any of our patients with xerostomia. At present, therefore, we cannot predict whether the severity and/or duration of acid exposure in patients with xerostomia is sufficient to predispose to other complications of peptic esophagitis. Given that we observed relatively mild esophageal abnormalities after 2 or more years of xerostomia, strictures or other serious sequelae would seem to be unlikely prospects. On the basis of the current data, it appears reasonable to prevent acid production (Hz-receptor antagonists) or neutralize acid (antacids) in patients with xerostomia. Artificial saliva and sialagogues (especially, pilocarpine) [20] may also improve esophageal acid clearance. However, the relatively poor buffering capacity of artifical saliva (unpublished observations) may limit the usefulness of these substances in acid clearance. Fortunately, xerostomia is generally self-limited when due to irradiation or medications. Thus, the risk of esophageal injury should decline as spontaneous saliva production increases. An additional issue pertains to patients with preexisting gastroesophageal reflux who develop xerostomia. This subgroup of patients may require more intensive protective measures. The superimposition of salivary deficiency in these individuals could conceivably further increase the likelihood of esophageal dysfunction. June
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ACKNOWLEDGMENT We wish to thank Drs. Louis Loscalzo (Head and Neck Surgery) Lehrer (Radiation Therapy) for referring patients with xerostomia.
and therapy. Ann Intern Med 1982; 97: 93-103. 10. Ahtaridis G, Snape WJ, Cohen S. Lower esophageal sphincter pressure as an index of gastroesophageal acid reflux. Dig Dis Sci 1981; 26: 993-6. 11. Behar J, Sheahan DC. Histologic abnormalities in reflux esophagitis. Arch Pathol 1975; 99: 387-91. 12. Winans CS. Diagnostic evaluation of esophageal function. In: Proceedings of the Second International Symposium on the Esophagus and Gastroesophageal Junction, Ixtapa, Mexico, March 20-23. 1978: 25-30. 13. Dent J, Dodds WJ. Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980; 65: 25667. 14. Dodds WJ. Dent J, Hogan WJ, eta/. Mechanism of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982; 307: 1547-52. 15. Ismail-Beigi F, Horton PF, Pope CE II. Histological consequences of gastroesophageal reflux in man. Gastroenterology 1970; 58: 163-74. 16. Fink SM. Barwick KW, Winchenbach CL, DeLuca V. McCallum RW. Reassessment of esophageal histology in normal subjects: a comparison of suction and endoscopic techniques. J Clin Gastroenterol 1983; 5: 177-83. 17. Knuff TE, Benjamin SB. Worshm GF, Hancock JE, Caste11 DO. Histologic evaluation of chronic gastroesophageal reflux. An evaluation of biopsy methods and diagnositc criteria. Dig Dis Sci 1984; 29: 194-201. 18.Zeitoun P. Pluot M, Vandromme L, Casola M. Evaluation by endoscopic biopsies of the histological criteria of reflux esophagitis. Gastroenterol Clin Biol 1987; 11: 6-11. 19. Streebny LM. Valdini A. Xerostomia: a neglected symptom. Arch Intern Med 1987; 147: 1333-7. 20. Greenspan D, Daniels TE. Effectiveness of pilocarpine in postradiation xerostomia. Cancer 1987; 59: 1123-5.
and Steven
REFERENCES 1. Helm JF, Dodds WJ, Hogan WJ. Soergel KH, Egide MS, Wood CM. Acid neutralizing capacity of human saliva. Gastroenterology 1982; 83: 69-74. 2. Helm JF, Dodds WJ, Riedel DR. Teeter BC, Hogan WJ. Arndorfer RC. Determinants of esophageal acid clearance in normal subjects. Gastroenterology 1983; 85: 607-12. 3. Helm JF, Dodds WJ, Pelt LR, Palmer DW, Hogan WJ, Teeter BC. Effect of esophageal emptying and saliva on clearance of acid from the esophagus. N Engl J Med 1984; 310: 284-8. 4. Silver LS. Worner TM, Korsten MA. Esophageal function in chronic alcoholics. Am J Gastroenterol 1986; 81: 423-7. 5. Booth DG, Kemmerer WI, Skinner DB. Acid clearing from the distal esophagus. Arch Surg 1968; 96: 731-4. 6. Kantrowitz PA, Corson JG, Fleishli DJ. Skinner DB. Measurement of gastroesophageal reflux. Gastroenterology 1968; 56: 666-73. 7. Johnson LF, DeMeester TR. Development of the 24hour intraesophageal pH monitoring composite scoring system. In: DeMeester TR, Skinner DB, eds. Esophageal disorders: pathophysiology and therapy. New York: Raven Press, 1985: 561-70. 8. Korsten MA, WornerTM, Feinman L, Shaw S, Federman Q. Balloon cytology in screening of asymptomatic alcoholics for esophageal cancer. Dig Dis Sci 1985; 30: 845-51. 9. Richter JB, Caste11 DO. Gastroesophageal reflux: pathogenesis, diagnosis,
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