Symposium on Gastroenterology for Internists

Gastroesophageal Refl ux Robert S. Fisher, M.D., * and Sidney Cohen, M.D. **

Gastroesophageal reflux, one of the most prevalent gastrointestinal disorders, may be defined as the retrograde flow of gastric contents across an incompetent gastroesophageal junction into the esophagus. The fluid may include not only the secretions of the stomach, but also duodenal juice which may have backwashed across an incompetent pyloric antire flux mechanism. The overall effects of gastroesophageal reflux upon the esophageal mucosa reflect the influences of a variable mixture of hydrochloric acid, pepsin, bile salts, and pancreatic enzymes. The mere presence of gastroesophageal reflux does not necessarily imply disordered function. In fact, various studies have demonstrated gastroesophageal reflux in a significant proportion of asymptomatic individuals. 47 • 74. 113 What factors determine whether gastroesophageal reflux in a given instance is physiologic or pathologic? To date this question has not been answered adequately. It will require a careful examination of the antireflux mechanism at the gastroesophageal junction, the normal defense mechanism of the esophageal mucosa, and the composition and quantity of refluxed material.

GASTROESOPHAGEAL ANTI-REFLUX MECHANISM In the normal individual, a positive pressure gradient exists across the gastroesophageal junction from the positive-pressure abdominal cavity to the negative-pressure thoracic cavity, necessitating an antireflux mechanism to prevent gastric material from entering the esophagus. Before the demonstration of a physiologic lower esophageal sphincter (LES) in the vicinity of the gastroesophageal junction, the antireflux mechanism was attributed to mechanical resistance only. Factors implicated were the cardioesophageal angle, a diaphragmatic pinchcock mechanism, action of the phrenoesophagealligament, mucosal rosette formed by gastric folds, and distal para-esophageal pressure.19. 111. 123 'Associate Professor of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania "'Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Medical Clinics of North America- Vol. 62, No. 1, January 1978

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The junction of the esophagus and stomach in man is marked by a zone of elevated pressure which has been called the lower esophageal sphincter. 25 . 26. 83. 88 This sphincter is generally regarded as the major determinant of gastroesophageal competence. Its major purpose is to prevent regurgitation of gastric contents from a positive-pressure cavity into the esophagus. It must also open or relax when called upon to allow passage of food into the stomach. The concept of a physiologic lower esophageal sphincter is based upon recognition that the distal portion of the esophagus, although anatomically indistinct, functions differently than the proximal body of the esophagus. In contrast to the esophageal body which is at rest basally but contracts in response to swallowing or esophageal distention, the lower esophageal sphincter is tonically contracted in the basal state and relaxes with swallowing or esophageal distention. 26 The reciprocal activity of the distal esophageal segment. compared to the body of the esophagus and the stomach is the major evidence for a physiologic lower esophageal sphincter mechanism. Studies performed on circular muscle strips from the distal esophagus, stomach, and lower esophageal sphincter have provided confirmatory evidence for the existence of a physiological lower esophageal sphincter differing from adjacent esophageal and gastric muscle. 25 . 26. 83.124 In the basal state in man, the lower esophageal sphincter is a 2 to 5 cm zone of elevated intraluminal pressure. In normals, this resting pressure when measured using infused, open-tipped recording catheters is 12 to 30 mm Hg above the intra-abdominal pressure level. Lower esophageal sphincter pressure, as measured using infused catheters, is an excellent index of the strength of the gastroesophageal antireflux mechanism 28 and correlates inversely with the quantity of gastroesophageal reflux. 48 Our understanding ofthe factors regulating basal lower esophageal sphincter strength is not entirely clear at the present time. Hormonal, neural, and mechanical mechanisms for regulating resting sphincter tone have been proposed. Basal lower esophageal sphincter pressure has been shown to change in response to various physiologic stimuli: These adaptive alterations in lower esophageal sphincter pressure can be divided into two major categories: (1) hormonal responses to food ingestion;91. 97. 98. 99 and (2) reflex changes in response to alterations in intra-abdominal pressure. 29 . 39. 58. 82 The changes in lower esophageal sphincter pressure which occur in response to ingestion of food are thought by some to be secondary to alterations in serum concentrations of the gastrointestinal hormones. In normal subjects, some have shown that increased intraabdominal pressure is associated with an even greater increase in lower esophageal sphincter pressure. 29 . 58. 82 This important adaptive response is probably operative in preventing gastroesophageal reflux during many daily activities. Mediation by a cholinergic reflex arc has been proposed. 81 To date, all gastrointestinal hormones studied have been demonstrated to alter lower esophageal sphincter pressure. Gastrin and motilin increase the pressure,22. 23. 50. 83 whereas secretin,30.84 cholecystokinin,106 and glucagon 72 decrease the pressure. These hormonal effects occur during their exogenous administration. Hormonal actions under

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physiological conditions have been more difficult to demonstrate because the amount of hormone released and the time .course of release in each subject during endogenous stimulation are variable. B4• 77. 91 However, feeding of a meal and the intragastric or intraduodenal instillation offood products alter lower esophageal sphincter pressure, presumably through a hormone-mediated mechanism. 99 Neural factors cannot .be excluded under these study conditions, but it seems unlikely that different food products would stimulate different nerve types. In summary, most observers would agree that a physiological lower esophageal sphincter is present at the gastroesophagealjunction. In addition, there is general agreement that the lower esophageal sphincter plays a major role in the prevention of gastroesophageal reflux. However, the regulation of both the resting sphincter tone and the adaptive changes in lower esophageal sphincter pressures to physiological stimuli remain the subject of great controversy.

PATHOGENESIS OF REFLUX ESOPHAGITIS Some studies have demonstrated that a significant proportion of asymptomatic normal subjects will have short bursts of gastroesophageal . reflux in either the upright or the supine positions. 45 • 73. 103 These observations would suggest that esophagitis is a multifactorial disorder not dependent solely on the presence or absence of gastroesophageal reflux (Table 1). Tissue Resistance Little is known about the tissue resistance of the esophageal mucosa. Several studies have demonstrated that its stratified squamous epithelium is very sensitive to the digestive action of gastric juice. 41 • 53. 7B Table 1. Pathogenesis of Reflux Esophagitis TISSUE RESISTANCE

Stratified squamous epithelium Esophageal secretions Barrier to H+ ion back diffusion Cell denudation and regeneration

AGGRESSIVE FACTORS

Acid Pepsin Bile Salts Pancreatic enzymes

DEFENSIVE FACTORS

Saliva Esophageal clearance Gastric emptying Pyloric anti-reflux mechanism Gastroesophageal anti-reflux mechanism

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In contrast, the deeper layers of the esophageal mucosa are more resistant to gastric juice as evidenced by the relative infrequency of true esophageal ulcers and perforation. 3s When compared to other regions of the gastrointestinal tract, few secretions are produced in the esophagus to either buffer refluxed acid or inactivate pepsin. The normal esophageal mucosa, like that of the stomach, is relatively impermeable to hydrogen ion. This feature can be altered by toxic agents such as bile salts. 53. 109 Little information is available ahout the cell denudation and regeneration of the esophageal mucosa. Certainly, the subject of esophageal tissue resistance needs further investigation.

Aggressive Factors Damage to the esophageal mucosa should correlate with both the composition and the quantity of material which refluxes into the esophagus. Acid and pepsiri have been accepted generally as the most important injurious agents. Hydrochloric acid alone in concentrations sufficient to reduce esophageal pH below 2.0 can cause protein denaturation within the esophageal mucosa. 53 Interestingly some studies in human patients have reported an increased incidence of esophagitis in patients with gastric acid hypersecretion. 24 ,54 However, patients with gastrinomas accompanied by very high acid secretion seldom develop esophagitis. 36 Gastric secretory studies have not been useful to predict which patients will develop esophagitis. 114 The addition of physiologic amounts of pepsin to the fluid which refluxes into the esophagus increases the amount of tissue injury due to the proteolytic properties of pepsin. 53 The corrosiv~ action of acid is complimented by pepsin which is activated at low pH's and has its maximal proteolytic activity at a pH around 2.0. Recently, the roles of bile salts52 , 62, 109 and pancreatic enzymes32 , 52, 101 in the pathogenesis of reflux esophagitis have been considered also. Esophagitis is not unusual after partial or total gastrectomy when secretion of both hydrochloric acid and pepsin is presumablyreduced. 61.129 In addition, several cases of "alkaline esophagitis" have been reported in patients afflicted with Addisonian pernicious anemia accompanied by absolute achlorhydria. 101 Experimentally, in primates it has been shown that bile salts increase the esophageal damage produced by gastric juice. 52 Bile salts in concentrations achieved in the normal stomach postprandially can increase the permeability of the esophageal mucosa to hydrogen ion and alter the transmucosal electrical potential difference, when brought in contact with the esophagus,l09 Increased concentrations of bile salts have been measured in the gastric aspirates of patients with reflux esophagitis. 75 , 121 Finally, the ecbolic component of the pancreatic juice is rich in proteolytic, lipolytic and amylytic enzymes. Their role in the development of reflux esophagitis has not been evaluated.

Defensive Factors It has been postulated that saliva might protect both the gastric and duodenal mucosa against ulceration. 90 Saliva is rich in bicarbonate, which may buffer acid, and sulfated polysaccharides, which possess antipeptic properties. Because of the paucity of secretions in the esophagus,

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the protective role of these salivary constituents might be important at this site. To date, this subject has had limited study. The contact time between the esophageal mucosa and the destructive elements in the fluid may be of great importance. Studies employing 24 hour esophageal pH monitoring have demonstrated recently that the severity of symptoms correlates with the contact time. 20 , 73, so Contact time is determined not only by gastroesqphageal incompetence, but also by the esophageal clearance mechanism. 20 Esophageal clearance depends upon three major factors: gravity, esophageal peristalsis, and normal relaxation of the lower esophageal sphincter after deglutition. In normal subjects dry and wet swallows are followed by purposeful, lumen-obliterating, aborally propagated contractions which progress from the cricopharyngeus muscle to the lower esophageal sphincter. These are termed primary peristaltic contractions and are largely responsible for esophageal clearance after ingestion of a bolus of food. The esophagus also responds to local distention with contractions which are propagated primarily in an aboral direction. These are designated as secondary peristalsis. 110 , 117 Normal motor function of the distal esophagus achieves special significance in the patient who is sleeping in the recumbent position. In this situation, the gravity factor has been removed, and primary peristaltic contractions are reduced by the decreased incidence of swallowing during sleep.so Consequently, if and when gastroesophageal reflux takes place, esophageal clearance of the material is determined by secondary peristaltic contractions. It depends upon the generation of pressure gradients (propulsive forces) by esophageal contractions and the coordination of these contractions both with each other (peristalsis) and with relaxation of the lower esophageal sphincter. Some patients with reflux esophagitis have abnormal motility in the body of the distal esophagus, characterized by feeble, repetitive, or nonprogressive contractions. 2, 100 This may impair esophageal clearance and increase mucosal contact time with destructive elements. It has been customary to attribute the distal esophageal motor disorder which frequently accompanies reflux esophagitis to inflammation of the muscularis secondary to gastroesophageal reflux of corrosive agents.37. 62, 63 Recently, it has been demonstrated in cats that irritation of the esophageal mucosa can cause gastroesophageal incompetence41 and, therefore, may induce gastroesophageal reflux. When viewed from this perspective, gastroesophageal reflux may create a cycle whereby it produces inflammation of the esophageal mucosa penetrating to the muscularis. A motor disorder of the distal esophagus results which may impede esophageal clearance. The prolonged contact time between the esophageal mucosa and the destructive elements of the reflux ate may increase the severity of esophageal inflammation, further impairing the gastroesophageal antireflux mechanism and allowing greater quantities of gastric material to enter the esophagus. Thus, we have a self-propagating destructive mechanism to explain reflux esophagitis. The volume of gastric material available for reflux into the esophagus undoubtedly affects the quantity of gastroesophageal reflux. This volume is determined by the magnitude of gastric secretion, gastric emptying and duodenogastric reflux. Recently, delayed gastric emptying has been

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suggested as a significant factor in patients with primary reflux esophagitis. 68 In patients with heartburn, increased duodenogastric reflux, as demonstrated radiographically51 and by increased concentrations of bile salts in the gastric aspirate,75, 121 may play a role. Not only would duodenogastric reflux increase the gastric volume available for gastroesophageal reflux, but also it would place high concentrations of toxic bile salts in the stomach from which they could reflux into the esophagus. Pyloric reflux and bile salt toxicity have been suggested previously in the pathogenesis of gastric ulcer.44

CLINICAL PRESENTATION Although gastroesophageal reflux may occur in asymptomatic individuals, significant reflux is usually associated with symptoms. Initially symptoms are quite mild and patients do not seek medical advice. In fact, most patients can recall symptoms consistent with reflux esophagitis for at least 1 year prior to diagnosis. 22 The earliest and most common symptom of gastroesophageal reflux is heartburn, which may be defined as a burning retrosternal discomfort which radiates cephalad and is aggravated in the recumbent position. Usually, the discomfort is relieved promptly by the ingestion of antacids. When gastroesophageal incompetence is severe, maneuvers which elevate intra-abdominal pressure may induce or aggravate heartburn. Other typical symptoms of gastroesophageal reflux include regurgitation of sour or bitter gastric contents into the mouth frequently accompanied by paroxysms of coughing due to aspiration of fluid, and dysphagia for both solids and liquids because of motor dysfunction of the distal esophagus. Gastroesophageal reflux may lead to severe esophagitis with distal esophageal stricture formation, accompanied by more persistent dysphagia especially for solid foods. Significant weight loss may result from decreased nutritional intake. Occasionally, patients with reflux esophagitis may complain of odynophagia when secondary esophageal spasm exists. The clinical symptoms of iron-deficiency anemia resulting from occult blood loss from the damaged esophageal mucosa may be a major problem. Massive hemorrhage secondary to reflux esophagitis may occur also. The intensity of symptoms in reflux esophagitis may not correlate with the volume of reflux, the size of an accompanying hiatal hernia or the severity of endoscopic or histologic esophagitis. Evidence does indicate, however, that symptoms do correlate with contact time between the destructive elements of the material refluxed and the esophageal mucosa. 20 , 73, 80, 117 Patients with more severe symptoms demonstrate more frequent reflux episodes during which esophageal pH is below 4 and also show prolonged acid clearance times.

PRIMARY LOWER ESOPHAGEAL SPHINCTER INCOMPETENCE AND HIATAL HERNIA For many years, it has been known that heartburn and other reflux symptoms occur commonly in the presence of a sliding hiatal hernia. However, the relationship between hiatal hernia and gastroesophageal

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reflux is not a simple one. Up to 50 per cent of the general population have hiatal hernias, yet only 5 per cent complain of reflux symptoms. 40 , 120, 130 Heartburn and unequivocal symptoms of reflux have been described frequently in the absence of other clinical disorders including hiatus hernia. In this case the condition can be called primary lower esophageal sphincter incompetence. 45, 86 In hiatal hernia, reflux has been ascribed to various anatomic abnormalities which have been mentioned previously. However, much clinical and experimental evidence, accumulated over the past two decades in situations where accessory resistance factors have been disrupted, suggests that lower esophageal sphincter dysfunction is the major determinant of gastroesophageal incompetence. 24 , 28, 57, 127 As mentioned before, occasionally patients with reflux seem to have perfectly normal lower esophageal sphincter function. 11, 45, 47, 57,104 Although there is general agreement that, in gastroesophageal incompetence with or without hiatal hernia, lower esophageal sphincter dysfunction is the major cause of reflux, the pathophysiology of lower esophageal sphincter dysfunction remains an enigma. Recently, evidence has been presented to suggest that both decreased lower esophageal sphincter stimulation and decreased responsiveness of the lower esophageal sphincter are present. An impairment in the antral gastrinrelease mechanism, as evidenced by decreased serum gastrin concentrations and decreased integrated gastrin response following stimulation of gastrin release, has been demonstrated in patients with gastroesophageal reflux with and without hiatal hernia.27' 86, 87 Direct stimulation of the lower esophageal sphincter by synthetic pentagastrin or by cholinergic agents has produced decreased absolute responses in these same patients. 86 , 87 Furthermore, both basal pressure and responsiveness of the lower esophageal sphincter to hormonal and cholinergic stimulation may return to normal in some patients following surgical repair. 85 This applies to both primary lower esophageal sphincter incompetence and hiatal hernia with reflux. Others have reported improvement in gastroesophageal competence after surgery in the absence of improved function of the lower esophageal sphincter. 6 , 46, 96 These observations suggest that lower esophageal sphincter dysfunction may be reversible in some patients. Although a definitive explanation for surgically improved lower esophageal sphincter function is wanting, a change in the length-tension characteristics of the lower esophageal sphincter circular muscle may be of importance. 16

DIAGNOSTIC EVALUATION The evaluation of suspected gastroesophageal reflux should include a careful clinical history accompanied by appropriate use of specialized clinical tests. The symptom complex characteristic of reflux esophagitis has been discussed previously. Usually, the clinical presentation and rapid response to conventional therapy allow the physician to arrive at the proper diagnosis. However, on occasion, gastroesophageal reflux may produce an atypical clinical picture and the response to therapy may be unsatisfactory. It should be emphasized that primary motor disorders of the esophagus may mimic the clinical symptoms of gastroesophageal

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reflux if specific complaints are not elicited. In addition, cardiac, biliary, and gastroduodenal disorders are frequently associated with symptoms which are difficult to distinguish from those of reflux. In these situations, diagnostic testing may be helpful. The techniques available currently to evaluate these patients are discussed below. Not all patients will have abnormal results in all tests. The physician must consider the composite of all results in arriving at a diagnostic conclusion.

Barium Esophagography with Fluoroscopy, and Cine-esophagography The technique of barium esophagography is familiar to most of us. After barium is ingested, spot films of the esophagus and gastroesophagealjunction are taken. Through the use offluoroscopic examination, esophageal distensibility, esophageal contractions and gastroesophageal reflux can be evaluated. Various maneuvers intended to increase intra-abdominal pressure are employed to induce gastroesophageal reflux. Barium esophagography with fluoroscopy may detect hiatal hernias, esophageal strictures, esophageal motor disorders, and even mucosal abnormalities. Furthermore, reflux may be detected directly in severe cases. Unfortunately, fluoroscopy is insensitive, providing a diagnosis in less than 50 per cent of patients with reflux.105 The physician is totally dependent upon the radiologist for interpretation of reflux and choice of spot films. Like fluoroscopy, cine-esophagography detects gastroesophageal reflux directly. In addition, a record of the entire examination is available at any time for review by the referring or consulting physician. Unfortunately, the equipment necessary for cineesophagography may not be available at all hospitals. The amount of radiation exposure to the patien t is significant; and reflux is detected only in about 70 per cent of symptomatic patients. 7 EsophageruEndoscopy Visual evaluation of the esophageal mucosa is accomplished by endoscopic examination. The endoscopic criteria for esophagitis are hyperemia, linear erosions, friability, exudation, bleeding, ulcerations, or stricture.!' 7. 59. 78. 108 It has now been demonstrated that many patients with symptomatic gastroesophageal reflux will have a normal appearing esophageal mucosa. 69 Furthermore, it must be emphasized that endoscopy detects an inflamed esophageal mucosa, and not reflux. Undoubtedly, ingestion of corrosive or toxic materials could produce a similar endoscopic appearance to what is seen in reflux esophagitis. Esophageru ~ucosru Biopsy Like endoscopy, mucosal biopsy is an indirect test of gastroesophageal reflux. The question answered is whether the esophageal mucosa is inflamed and not whether gastroesophageal reflux produced the inflammation. Esophageal mucosal biopsy can be performed under direct vision with either a pinch forceps, passed through the biopsy channel of the endoscope, or a specialized instrument for obtaining larger samples of mucosa passed alongside the endoscope. Samples obtained with the pinch forceps are difficult to orient and interpret, except in severe

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cases. Consequently, they are frequently normal in patients with documented symptomatic reflux. In contrast, multiple suction biopsies of either inflamed esophageal mucosa or normal appearing mucosa provide a more sensitive technique for obtaining indirect evidence of gastroesophageal reflux. 69• 7o In addition to superficial inflammatory changes, newer criteria for esophagitis which can be applied to tissue specimens obtained by suction biopsy include an increased thickness of the basal cell zone and abnormal proximity of the dermal papillae to the epithelial surface. There is some controversy concerning the diagnostic importance of these more subtle changes, but most investigators feel that their absence excludes the presence of significant gastroesophageal reflux. 69. 70. 79. 128

Esophageal Manometry This technique employs either perfused catheters or direct intraluminal transducers to measure lower esophageal sphincter pressure and esophageal contractions. After the tube assembly is passed into the stomach, intraluminal pressures are recorded continuously as it is withdrawn by increments from stomach to pharynx. The advantages of esophageal manometry are that it can demonstrate a potential etiology for reflux symptoms (Le., lower esophageal sphincter pressure less than 10 mm Hg), and it can detect motor dysfunction in the body of the esophagus which may be secondary to gastroesophageal reflux. Although studies have demonstrated repeatedly that lower esophageal sphincter pressure tends to be subnormal in patients with reflux, 29. 57. 104 there is some overlap between lower esophageal sphincter pressures in normal subjects and symptomatic patients. Recently, several authors have detected a significant incidence of reflux in the presence of normal lower esophageal sphincter pressure. 11 • 47. 69. 79. 95. 119. 133 In addition, esophageal peristalsis is frequently normal in reflux patients. 100. 110 Perhaps, these observations are merely a reflection of the heterogeneity of patients with gastroesophageal reflux. In some, gastroesophageal reflux may be due to lower esophageal sphincter dysfunction, but in others mechanical factors may be more important. Acid Perfusion Test This test is useful to decide if thoracic symptoms are related to esophageal disease. After a tube is positioned, the mid-esophagus is perfused alternately with normal saline, 0.1 N hydrochloric acid, and again with normal saline. It is positive if there is a strong correlation between the occurrence of heartburn or retrosternal pain and the period of hydrochloric acid perfusion. Some have reported good correlation between reflux symptoms and the induction of heartburn by acid perfusion. 12 Others have not obtained such impressive results. 47 This test has some disadvantages. Intubation is required. It detects, not reflux, but acidsensitivity of the esophageal mucosa. Recent reports have suggested a significant incidence of false positives with an acid-sensitive gastric or duodenal mucosa. 33

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Esophageal pH Monitoring Diagnostic maneuvers using measurement of esophageal pH all require positioning of a pH electrode 4 to 5 cm above the lower esophageal sphincter. In the standard acid-reflux test, esophageal pH is measured after instilling 0.1 N hydrochloric acid into the stomach. A positive test is indicated by a drop in pH below 4,125,126 Some have varied this test by employing different maneuvers to increase intra-abdominal pressure. 47 The acid-reflux test has the advantages of being a sensitive, semiquantitative technique which detects reflux directly and correlates very well with symptoms. Recently, 24 hour and overnight pH monitoring have been used successfully to study patient with reflux symptoms. 73, 80, 119 Such prolonged esophageal pH measurement seems to be more useful as a research tool than as a clinically useful test. Acid-clearance testing has also been studied with the belief that deficient acid clearance may contribute to the development of esophagitis in patients with gastroesophageal reflux. 7,20,79 After ingestion of 15 ml of 0.1 N hydrochloric acid, the number of swallows at 30 second intervals necessary to restore esophageal pH to 4 or above is determined. Normally, less than 4 swallows are required, and more than 10 swallows suggests an abnormality. Gastroesophageal Scintiscanning A recent addition to the diagnostic armamentarium for gastroesophageal reflux is scintiscanning. 47 This technique has been reported to provide, not only a sensitive, direct method for detecting reflux, but also a quantitative estimate of reflux. Serial scintiscans are obtained with the patient in the supine position after ingestion of a solution containing a radionucleotide marker. Scans are obtained as the intra-abdominal pressure is increased in increments. The gastroesophageal scintiscan is considered positive for reflux if the esophagus is visualized in any of the scintiscans. It has been reported that the sensitivity of the procedure compares favorably with that of other tests commonly employed to evaluate reflux. Quantitation of reflux can also be accomplished using this technique by counting radioactivity over selected esophageal and gastric areas of interest. This technique has several potential advantages: first, reflux is detected directly; second, intubation is unnecessary; third, it is highly sensitive; fourth, the equipment necessary for its performance is present in most Nuclear Medicine Sections.

TREATMENT OF SYMPTOMATIC GASTROESOPHAGEAL REFLUX Many therapeutic modalities have been employed to prevent or treat the symptoms associated with gastroesophageal reflux (Table 2). In this section the rationale behind these treatments will be outlined.

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Table 2. Treatment of Gastroesophageal Reflux 1. Decrease gastroesophageal pressure gradient

Weight reduction Avoid maneuvers which increase intra-abdominal pressure Elevate head of bed

2. Neutralize acid or decrease acid secretion Avoid agent which may increase gastric secretion Regular equal meals Antacids Alginic acid with antacids H 2-receptor antagonists 3. Avoid agents which decrease lower esophageal sphincter pressure Decrease fat intake A void chocolate Do not smoke Avoid anti-cholinergic agents Avoid xanthine-containing medications Avoid alcohol 4. Increase resistance to gastroesophageal reflux Bethanechol Alginic acid with antacids Antacids Metoclopramide Surgical procedures

Decreasing the Gastroesophageal Pressure Gradient Clinical experience suggests that weight reduction in obese patients is often successful in decreasing the symptoms associated with gastroesophageal reflux. 4 , 98, 99 Although controlled clinical studies are not available, it has been postulated that intra-abdominal pressure and, therefore, the gastroesophageal pressure gradient may be elevated in obese patients, especially in the supine position. For similar reasons tight garments such as girdles might increase reflux. Various maneuvers performed during everyday life may increase intra-abdominal pressure and increase reflux. Included here would be excessive straining during defecation, bending at the waist, and straining to lift heavy objects. These activities should be minimized or eliminated when possible. Probably the most effective therapeutic maneuver in this category is elevation of the head of the bed with blocks which decreases nocturnal reflux. 73 The placement of blocks under the legs at the head of the bed is more effective than propping the patient's head under extra pillows. The use of a hospital bed which allows variable chest elevation to the patient's comfort is probably the most effective means of elevating the trunk, but is quite expensive. The rationale behind these methods is to use gravity or hydrostatic pressure to diminish the gastroesophageal pressure gradient. 49

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Neutralizing Acid or Decreasing Acid Secretion Measures which may be useful to decrease acid secretory response to food include the avoidance of dietary constituents such as coffee and spicy foods and the ingestion of small, regular bland feedings. Antacids buffer gastric acid and, therefore, should be useful in the treatment of heartburn. Abundant testimonial evidence documenting this action is available, but few controlled studies have been reported. Antacids have a dual mode of action in that lower esophageal sphincter pressure is increased also after their administration. 23 • 49 Thus, the resistance to gastroesophageal reflux is increased and the quantity of reflux is diminished. Recently, antacids have been combined with alginic acid, an agent which forms a viscous foam and floats upon the liquid meniscus within the stomach. 3 • 94.118 Although the amount of antacid within this preparation is insufficient to neutralize all of the acid within the stomach, evidence is available to show that most of the material which refluxes into the esophagus is neutralized. Like antacids alone, this combination has a dual mode of action. 49 Because of the mixing of this viscous preparation with the gastric juice, resistance is increased and the quantity of reflux is reduced. Lower esophageal sphincter pressure remains unchanged. Most recently, attention has been focused on a new class of pharmacologic agents, the histamine-2 receptor antagonists. 56.89.107.132 These agents block the histamine-2 receptors within the gastrointestinal tract, namely the stomach, and inhibit profoundly gastric acid secretion without producing significant pulmonary or central nervous system side effects. The H2 antagonists do not alter lower esophageal sphincter pressure in man. Clinical trials with these agents are not completed. A voiding Agents Which Decrease Lower Esophageal Sphincter Pressure Many agents, either ingested in the diet or taken as medical treatment, may decrease lower esophageal sphincter pressure and increase the quantity of reflux. Fatty meals have been demonstrated to decrease sphincter pressure, presumably by releasing cholecystokinin from the small bowel mucosa. This action correlates well with increased symptoms after fatty meals. 98.99 Ingestion of chocolate can also aggravate symptoms of reflux. 5 • 131 Presumably, this is due to the high content of xanthines within chocolate. Xanthines are strong inhibitors of phosphodiesterase within the cells and, therefore, may increase the concentration of cyclicAMP at the lower esophageal sphincter smooth muscle receptor sites. 55 Smoking tobacco has been observed to diminish resting lower esophageal sphincter pressure presumably through the action of nicotine. 34 • 115 The administration of anticholinergic medications may aggravate the symptoms of gastroesophageal reflux by increasing the quantity of reflux. 48 As discussed previously, cholinergic neural mechanisms may have some importance in the maintenance of resting lower esophageal sphincter pressure and the mediation of the adaptive responses of the lower esophageal sphincter to changes in intra-abdominal pressure. Lastly, alcohol in very high doses may decrease resting lower esophageal sphincter pressure and disrupt the orderly contraction of the esophagus. 67

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Increasing Resistance to Gastroesophageal ReHux This category of treatment modalities includes agents which decrease the quantity of reflux by increasing resistance at the gastroesophageal junction. Bethanechol, a cholinomimetic agent, has been demonstrated to increase lower esophageal sphincter pressure in both normal subjects and patients with symptomatic reflux. 15, 49 Clinical improvement during treatment with bethanechol has been reported. 43 A potential problem with cholinomimetic therapy might be increased acid secretion. The ability of antacids 23 ,49 and the combination of antacids with alginic acid 44 to increase gastroesophageal resistance and retard reflux has been mentioned earlier. However, the mechanisms by which this is accomplished are quite different. Antacids, if given in sufficient amount, increase lower esophageal sphincter pressure about 20 to 30 minutes after their administration. 23 , 49. 64. 77 The exact mechanism by which antacids produce increased sphincter pressure is unknown. Some have suggested that release of gastrin from the antral mucosa is responsible,23 but this explanation is not accepted unequivocally.64, 77 Alginic acid seems to decrease reflux by means of its viscosity which in effect serves as a mechanical barrier to reflux which is independent of the lower esophageal sphincter. 49 Metoclopramide is a new pharmacologic agent which produces a smooth muscle contraction, by direct smooth muscle stimulation and a dopaminergicblocking mechanism. 9. 17. 18.42.71. 122 Its potentially beneficial effects for treating patients with symptomatic gastroesophageal reflux include its ability to increase lower esophageal sphincter pressure, to accelerate esophageal clearance, and to increase gastric emptying. 10. 31. 60. 93. 116 A recent clinical trial has suggested that metoclopramide, administered orally, might decrease symptoms in patients with reflux esophagitis. 92 Surgical Treatment of ReHux Esophagitis In recent years there has been a resurgence of interest in antireflux surgery to prevent gastroesophageal reflux. Newer procedures which are currently utilized include the Nissen fundoplication, 8 the Hill transabdominal gastropexy,6S. 66 and the Belsey Mark IV transthoracic repair. 102 In general, these operations employ reduction of hiatal hernia, calibration of the gastroesophageal junction, restoration of an intra-abdominal segment of esophagus, partial or total imbrication of the stomach around the intra-abdominal esophagus and fixation of the gastroesophageal junction below the diaphragm. The indications for surgery have been failure to relieve symptoms with vigorous medical management and severe complications of gastroesophageal reflux such as hemorrhage, stricture formation, esophageal ulcer, or repeated episodes of aspiration. The surgical reduction of symptoms induced by reflux has been attributed to increased resistance at the gastroesophageal junction, specifically to increased lower esophageal sphincter pressure. However, whether this improvement is due to improved lower esophageal sphincter pressure alone or alterations of other mechanical factors remains controversial. 46 Undoubtedly, the results achieved with these surgical techniques have been encouraging, but long tenn follow-up is not available.

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