Wednesday, March 7, 2007

Gastroesophageal Reflux Disease: Diagnosis and Management

Gastroesophageal reflux disease (GERD) is a chronic, relapsing condition with associated morbidity and an adverse impact on quality of life. The disease is common, with an estimated lifetime prevalence of 25 to 35 percent in the U.S. population. GERD can usually be diagnosed based on the clinical presentation alone. In some patients, however, the diagnosis may require endoscopy and, rarely, ambulatory pH monitoring. Management includes lifestyle modifications and pharmacologic therapy; refractory disease requires surgery. The therapeutic goals are to control symptoms, heal esophagitis and maintain remission so that morbidity is decreased and quality of life is improved.
Gastroesophageal reflux is a normal physiologic event that may occur as often as once an hour.1 The causes for the transformation of this normal process into a chronic, relapsing illness have not been well defined, but numerous factors are thought to be involved. The symptoms of gastroesophageal reflux disease (GERD) vary from patient to patient, and multiple diagnostic tests and treatments are available. Given the variability of symptoms and the prevalence of GERD, family physicians need to understand the presentations, diagnosis and treatments of this illness.

Overview of the Problem

As many as 10 percent of Americans have episodes of heartburn (pyrosis) every day, and 44 percent have symptoms at least once a month.1,2 In all, GERD affects an estimated 25 to 35 percent of the U.S. population.3 Even though many persons with GERD may not seek medical care, annual health care costs related to this disease are still high.

Psychologic well-being questionnaires have found that patients with GERD can have a worse quality of life than some patients with menopausal symptoms, peptic ulcer disease, angina or congestive heart failure.4 The combination of symptoms, dietary restrictions and functional limitations can take a toll on overall sense of well-being.5

The natural course of GERD involves a decrease in symptoms despite the persistence of reflux. Three fourths of conservatively treated patients experience a lessening of symptoms over many years, even though two thirds of them still have objective evidence of the disease.2

Esophagitis, a complication of GERD, tends to become a relapsing, chronic condition. It recurs in 50 to 80 percent of affected patients within six to 12 months after the discontinuation of pharmacologic therapy.5 Other complications of GERD include strictures, ulcerations and Barrett's esophagus (progressive replacement of distal eroded squamous mucosa with metaplastic gastric epithelium). Patients with Barrett's esophagus have a 30 to 125 times greater risk of developing adenocarcinoma of the esophagus (even though the overall risk remains quite low).3 Younger age at onset and longer duration of symptoms seem to increase the risk of malignancy.3

Treatment of GERD associated with Barrett's esophagus has not been shown to eliminate the metaplasia of that condition or the risk of malignancy. Consequently, patients with Barrett's esophagus require periodic endoscopic biopsy to assess esophageal tissue for malignant changes.6


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In the diagnosis of GERD, response of symptoms to treatment with a proton pump inhibitor is as sensitive and specific as the results of 24-hour pH monitoring.
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GERD is thought to have a multifactorial etiology rather than a single cause. Contributing factors include the caustic materials that are refluxed, a breakdown in the defense mechanisms of the esophagus and a functional abnormality that results in reflux.

Offending Agents
Stomach secretions and contents are naturally at a lower pH than the normal esophageal environment. If these more acidic substances are not cleared rapidly from the esophagus, they can harm esophageal tissue. Acidic gastric material is undoubtedly the primary offending agent in the development of GERD, with duration of exposure being a key factor.1

The role of bile acids from the duodenum is also being investigated. As many as 60 percent of patients with GERD reflux both gastric and duodenal juices.7 Although definite proof is lacking, bile acid reflux may be the reason that more severe esophagitis can be difficult to heal despite adequate suppression of gastric acid secretion.7

Defects and Abnormalities
The lower esophageal sphincter normally works in conjunction with the diaphragm to create a physical barrier against the entry of gastric contents into the esophagus.4 Transient relaxation of this sphincter may occur more often in patients with GERD.1

Esophageal motility disorders and delayed gastric emptying may also be factors in the development of GERD.1,4 The role of delayed gastric emptying remains controversial, but patients with gastroparesis have been shown to have a predisposition to reflux.8

The contribution of hiatal hernia to GERD is another source of controversy. Although the incidence of prolonged reflux appears to be increased with hiatal hernia, patients may have a hiatal hernia without reflux or reflux without a hernia.9

Other possible causal factors in GERD include delayed clearance of physiologic reflux by saliva, decreased secretion of bicarbonate by esophageal submucosal glands and attenuated ability of the cells lining the esophagus to resist acid injury.1


Clinical Presentation
When patients present with typical symptoms and no complications, the diagnosis of GERD is usually straightforward. The classic symptoms are heartburn and regurgitation, which may also include dysphagia.10

In the absence of classic symptoms, GERD becomes more difficult to diagnose. Other symptoms that may be caused by GERD are atypical chest pain, hoarseness, nausea, cough, odynophagia and asthma.11 Symptoms that may indicate a more serious problem, such as chest pain (possible cardiac causes), dysphagia, odynophagia and weight loss (possible esophageal stricture or cancer), require more extensive investigation before the diagnosis of GERD can be established. Diagnostic tests are used when the diagnosis is in doubt or complications are a concern.

Response to Omeprazole
A recent study12 demonstrated a potential role for a proton pump inhibitor, omeprazole (Prilosec), in the diagnosis of GERD. The response of symptoms to omeprazole, in a dosage of 40 mg per day for 14 days, was shown to be about as specific and sensitive for the diagnosis of GERD as the results of 24-hour pH monitoring. Because of the efficacy of omeprazole in relieving reflux symptoms, failure to respond to this proton pump inhibitor warrants investigation of other possible causes for a patient's symptoms.

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Lifestyle modifications should be emphasized and incorporated into all stages of treatment.
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Radiologic Findings
Only one third of patients with GERD have radiologic signs of esophagitis.13 Findings include erosions and ulcerations, strictures, hiatal hernia, thickening of mucosal folds and poor distensibility.13,14 Only a minority of patients with documented abnormal pH have radiographically evident esophagitis.13 Consequently, a radiographic study is not the test of choice for the diagnosis of GERD.

Endoscopy is useful for diagnosing the complications of GERD, such as Barrett's esophagus, esophagitis and strictures, but it is not sensitive for diagnosis of GERD itself. Only 50 percent of patients with GERD manifest macroscopic evidence on endoscopy.12

Ambulatory pH Monitoring
Ambulatory pH monitoring is generally considered the diagnostic gold standard for use in patients with GERD. In this study, a pH monitor is placed in the esophagus above the lower esophageal sphincter, and the pH is recorded at given moments in time. Over the 24-hour test period, the patient writes down the time and situation in which symptoms occur, in the hope that symptoms can be correlated with the lowering of esophageal pH that occurs with reflux.

Esophageal pH monitoring may not be available in some areas. Furthermore, the test is time-consuming, and it can be inconvenient or troublesome for the patient. In addition, pH monitoring requires good technical placement of the probe and experienced interpretation of the results.10,12

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Management Stages for Gastroesophageal Reflux Disease
Figure 1
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FIGURE 1. Management of gastroesophageal reflux disease.


The management of GERD can be divided into five stages (Figure 1). Stages I through IV consist of medical management, and stage V entails surgical intervention. The ultimate goal of treatment is to minimize exposure of the esophagus to refluxate, thereby alleviating symptoms, healing the esophagus, preventing complications and maintaining remission.4,15

Most patients with GERD achieve adequate symptom control and esophageal healing through a combination of lifestyle modifications and drug therapy and therefore do not require surgical intervention. Antireflux surgery may be required in patients who continue to have severe symptoms, erosive esophagitis or disease complications despite adequate pharmacologic therapy.6,15

Stage I: Lifestyle Modifications
Lifestyle modifications are a key component in the management of GERD and should be incorporated into all treatment stages. Modifications include elevating the head of the bed by six inches, decreasing fat intake, stopping smoking, reducing alcohol consumption, losing weight, avoiding recumbency for three hours postprandially and not consuming large meals and certain types of food (Table 1).5,16

Despite the lack of extensive clinical data supporting the effectiveness of lifestyle modifications as sole therapy, patients with GERD experience relief of mild to severe symptoms by incorporating these changes into their daily routine.14,17 Many patients view lifestyle modifications as being somewhat inhibitive and impractical. However, it should be emphasized that stopping smoking and reducing fat and alcohol consumption not only improve GERD symptoms but also improve cardiopulmonary health and reduce the risk of certain types of cancer.17

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Dietary Factors Associated with Increased Reflux Symptoms*

Caffeinated products Chocolate Tomato-based products
Peppermint Spicy foods Alcohol
Fatty Foods Citrus fruits and juices

*--Smoking also increases reflux and aggravates gastroesophageal reflux disease.

Information from Fennerty MB, Castell D, Fendrick AM, Halpern M, Johnson D, Kahrilas PJ, et al. The diagnosis and treatment of gastroesophageal reflux disease in a managed care environment: suggested disease management guidelines. Arch Intern Med 1996;156:477-84, and DeVault KR, Castell DO. Guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Arch Intern Med 1995;155:2165-73.

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Stage II: 'As-Needed' Pharmacologic Therapy
In addition to lifestyle modifications, patients with mild symptoms often require periodic drug therapy for symptom relief. This is typically achieved through the as-needed use of antacids, alginic acid (a component of antacid products such as Gaviscon) or over-the-counter histamine H2-receptor blockers.

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Adverse Effects of Antacids

Potential adverse effects
Aluminum salts • Constipation
• Accumulation in patients with renal impairment
• Hypophosphatemia
• Osteomalacia (rare)
Calcium salts • Constipation
• Milk-alkali syndrome with high doses
• Rebound hyperacidity (depends on dosage)
Magnesium salts • Diarrhea
• Accumulation in patients with renal impairment
Sodium bicarbonate* • Milk-alkali syndrome with high doses
Magnesium- aluminum combinations • Minor changes in bowel function

*--Antacids containing sodium bicarbonate should be avoided in sodium-restricted patients, such as those with hypertension or congestive heart failure.
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Antacids and Alginic Acid. Antacids remain the drugs of choice for quick relief of symptoms associated with GERD.17 These agents act primarily by rapidly increasing the pH of the gastric refluxate. Although antacids are effective in relieving symptoms, they are not used as sole agents for achieving esophageal healing because of the high dosage requirements and consequent lack of patient compliance.

When antacids are included in the therapeutic regimen, patients must be instructed in appropriate dosing. For maximum relief of symptoms, antacids should be used as needed and should be taken immediately after meals if symptoms occur.

Patients treated with antacids also need to be aware of potential adverse effects (Table 2) and drug interactions. Antacids can interact with a number of drugs, including fluoroquinolones, tetracycline and ferrous sulfate. The mechanism may be alteration of the gastric pH, increase of the urinary pH or adsorption of the concomitant agent with resultant alteration of bioavailability.18

Alginic acid is a component of various antacid products. Rather than neutralizing gastric acid, it reacts with sodium bicarbonate in saliva to form sodium alginate. The sodium alginate floats on top of the gastric contents where it acts as a mechanical barrier, minimizing exposure of the esophagus to refluxate. Although alginic acid is theoretically beneficial, it does not appear to be clinically superior to antacids alone. Furthermore, antacid products containing alginic acid tend to be expensive.

Over-the-Counter H2-Receptor Blockers. Four over-the-counter H2-receptor blockers are currently available in the United States (Table 3) These agents are indicated for the prevention and relief of heartburn, acid indigestion and sour stomach. They are available in half of the dosage strength of the prescription products. Although over-the-counter H2-receptor blockers do not act as rapidly as antacids, they provide longer relief of symptoms. Because of their slower onset of action, H2-receptor blockers are primarily used to prevent GERD symptoms.

Stage III: Initiation and Titration of Scheduled Pharmacologic Therapy
Instead of as-needed treatment, scheduled pharmacologic therapy is required in patients who have moderate to severe symptoms with or without documented erosive esophagitis.5,16 In this treatment stage, suppression of gastric acid through the use of pharmacologic agents remains the primary approach for reducing reflux symptoms, healing esophagitis and maintaining remission.

Clinical data indicate that esophageal healing is influenced by both the degree and duration of gastric acid suppression.19,20 Healing rates increase in relation to the length of time that the intragastric pH remains above 4.19 The agents used in stage III treatment of GERD include scheduled H2-receptor blockers, prokinetic agents and proton pump inhibitors. (Table 3). The choice of agent depends primarily on the severity of symptoms and the presence or absence of esophagitis.

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Medications Used in the Treatment of Gastroesophageal Reflux Disease

Cost (generic price)*
Antacids (liquids and tablets) As needed $ 1 to 5
Over-the-counter H2-receptor blockers

Nizatadine (Axid AR) 75 mg twice daily as needed 9†

Famotidine (Pepcid AC) 10 mg twice daily as needed 9†

Cimetidine (Tagamet HB) 200 mg twice daily as needed 10†

Ranitidine (Zantac 75) 75 mg twice daily as needed 9†
Prokinetic agents

Cisapride (Propulsid) 10 mg two or four times daily 45 to 90

20 mg four times daily 174

Metoclopramide (Reglan) 10 mg four times daily 92 (20 to 30)
H2-receptor blockers

Cimetidine (Tagamet) 400 mg twice daily 101 (82)

800 mg twice daily 179 (132 to 153)

Famotidine (Pepcid) 20 mg twice daily 99

40 mg twice daily 185

Nizatadine (Axid) 150 mg twice daily 96

Ranitidine (Zantac) 150 mg two‡ to four times daily 99 (88 to 177)

300 mg twice daily 180 (162)
Proton pump inhibitors

Lansoprazole (Prevacid) 15 mg once daily 105

30 mg once daily 107

Omeprazole (Prilosec) 10 mg once daily 104

20 mg once daily 116

*--Estimated cost to the pharmacist based on average wholesale prices (rounded to the nearest dollar) for one month's supply unless otherwise noted, in Red book. Montvale, N.J.: Medical Economics Data, 1998. Cost to the patient will be greater, depending on prescription filling fee.

†--For 30 tablets. Over-the-counter indications limit continued use of these products to two weeks or less.

‡--Brand-name dosage.

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H2-Receptor Blockers. Before proton pump inhibitors were introduced, H2-receptor blockers were the agents of choice for treating reflux symptoms and healing esophagitis. They remain the mainstay of pharmacologic treatment.

H2-receptor blockers act by inhibiting histamine stimulation of the gastric parietal cell, thereby suppressing gastric acid secretion.19 These agents only minimally inhibit parietal cell stimulation by gastrin and acetylcholine, and therefore are weak inhibitors of meal-stimulated acid secretion. They are most effective in suppressing nocturnal acid secretion.

When given in the standard dosages used for peptic ulcer disease, H2 -receptor blockers relieve the symptoms of mild to moderate GERD.16,20,21 However, standard dosages of these agents are not highly effective in healing esophagitis because acid secretion is not completely inhibited.20 When higher dosages and/or more frequent doses of H2 -receptor blockers are used, adequate symptom relief occurs in approximately 50 to 60 percent of patients, and esophageal healing occurs in approximately 50 percent of patients.4

In equivalent dosages, the various H2-receptor blockers are equally effective in providing symptom relief, healing esophagitis and maintaining remission. Selection of a particular agent is largely based on cost. Currently, only cimetidine (Tagamet) and ranitidine (Zantac) are available in generic preparations.

H2-receptor blockers are fairly well tolerated and rarely require discontinuation secondary to adverse effects. The most common adverse effects are headache, diarrhea and constipation. Drug interactions occur more frequently with cimetidine than with other H2-receptor blockers. The increase in drug interactions is related to the ability of cimetidine to inhibit the metabolism of drugs through various cytochrome P450 isoenzyme systems (Table 4).18

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Potential Drug Interactions with Cimetidine (Tagamet)*

Warfarin (Coumadin) Diazepam (Valium)
Phenytoin (Dilantin) Metronidazole (Flagyl)
Propranolol (Inderal) Lidocaine (Xylocaine)
Calcium channel blockers Theophylline
Chlordiazepoxide (Librium) Certain tricyclic antidepressants

*--Cimetidine reduces the hepatic metabolism and increases the drug levels of these drugs through an effect on certain microsomal enzyme systems.

Information from Welage LS, Berardi RR. Drug interactions with antiulcer agents: considerations in the treatment of acid-peptic disease. J Pharm Pract 1994;7:177-95.

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Prokinetic Agents. Rather than neutralizing acid, prokinetic agents increase both gastric emptying and lower esophageal sphincter pressure.6 Cisapride (Propulsid) acts by increasing acetylcholine concentrations in the myenteric plexus. Because of the cholinergic side effects associated with bethanechol (Urecholine) and the central nervous system side effects associated with metoclopramide (Reglan), these older prokinetic agents are no longer frequently prescribed.

In clinical trials, cisapride has been found to be equivalent to standard-dose H2-receptor blockers in relieving reflux symptoms and healing the esophagus.6,16,22 However, cisapride requires more frequent dosing and has a higher incidence of side effects and drug interactions.4

The side effects of cisapride are generally limited to abdominal cramping and diarrhea. According to recent labeling changes and an expanded black box warning, cisapride should not be used in conjunction with agents known to inhibit the cytochrome P450 3A4 isoenzyme system (Table 5).23

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Potential Drug Interactions with Cisapride (Propulsid)

Increase cisapride to dangerous blood levels* Predispose patients to fatal arrhythmias with cisapride†
Clarithromycin (Biaxin)
Troleandomycin (Tao)
Nefazodone (Serzone)
Fluconazole (Diflucan)
Itraconazole (Sporanox)
Ketoconazole (Nizoral)
Indinavir (Crixivan)
Ritonavir (Norvir)
Class 1A antiarrhythmics
Class III antiarrhythmics
Certain tricyclic antidepressants
Certain tetracyclic antidepressants
Certain antipsychotics

*--These drugs increase cisapride blood levels by inhibiting the cytochrome P450 3A4 enzymes that metabolize cisapride. This can lead to fatal cardiac arrhythmias.

†--Cisapride is contraindicated for concomitant use with medications that prolong the QT interval and thereby increase the risk for an arrhythmia. This list is not comprehensive.

Information from Propulsid. Package insert. Titusville, N.J.: Janssen Pharmaceutica Inc., 1998.

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Inhibition of the metabolism of cisapride and subsequent accumulation of the active drug can lead to prolongation of the QT interval and the ultimate development of serious, potentially fatal cardiac arrhythmias. Cisapride should also be avoided in patients who have a history of QT interval prolongation, who are taking medications known to increase the QT interval or who have conditions that may predispose them to develop arrhythmias.

The manufacturer of cisapride recommends that a baseline electrocardiogram be considered before cisapride therapy is initiated.23

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When equipotent doses are given, the various H2-receptor blockers do not differ in efficacy.
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Proton Pump Inhibitors. Omeprazole and lansoprazole (Prevacid) are the currently available proton pump inhibitors. These drugs strongly inhibit gastric acid secretion. They act by irreversibly inhibiting the H+-K+ adenosine triphosphatase pump of the parietal cell. By blocking the final common pathway of gastric acid secretion, the proton pump inhibitors provide a greater degree and duration of gastric acid suppression compared with H2-receptor blockers.19 Clinical trials16,20,22,24-26 have clearly shown that the proton pump inhibitors provide better symptom control, esophageal healing and maintenance of remission than either H2-receptor blockers or prokinetic agents.

Long-term use of proton pump inhibitors in humans has not been associated with an increased risk of gastric carcinoma, although this was initially a concern.24 Prolonged use of the drugs has been associated with gastric atrophy; however, atrophy is more likely to be a problem in patients infected with Helicobacter pylori.4,6

The proton pump inhibitors are fairly well tolerated. The most common side effects are nausea, diarrhea, constipation, headache and skin rash. Omeprazole and lansoprazole are more expensive than standard-dose H2-receptor blockers or prokinetic agents. However, when prescribed appropriately to patients with severe symptoms or refractory disease, the proton pump inhibitors are more cost-effective because of their higher healing and remission rates and the consequent prevention of complications.4

Combination Therapy. The use of combination drug therapy is not justified in most patients with GERD.5,27 The combination of an H2-receptor blocker and cisapride has been shown to provide better symptom relief and healing rates than treatment using either agent alone.5,22 However, compared to proton pump inhibitor therapy, this combined regimen is less effective and more costly, and it may be associated with an increased incidence of side effects and possible drug interactions.27 The combination of an antisecretory agent and a prokinetic agent may be appropriate in a patient with delayed gastric emptying, such as a diabetic patient with gastroparesis.

Summary of Stage III Treatment. In a patient with moderate to severe symptoms but no documented erosive esophagitis, pharmacologic therapy is generally initiated with an H2-receptor blocker or a prokinetic agent, and the targeted duration of therapy is eight to 12 weeks.

If the patient remains symptomatic, the dosage of the H2-receptor blocker is maximized, or therapy is changed to a proton pump inhibitor. Therapy should be continued for another eight to 12 weeks. As previously mentioned, the diagnosis should be reconsidered if the patient remains symptomatic on high-dose (40 mg) proton pump inhibitor therapy.

The patient with erosive esophagitis documented by endoscopy should be given omeprazole or lansoprazole as initial therapy because of the higher healing rates associated with proton pump inhibitors.

Stage IV: Maintenance Therapy
GERD has a high recurrence rate because no currently available pharmacologic agent is able to correct the underlying cause or causes of the disease. The need for maintenance therapy depends largely on the severity of the disease and the persistence of symptoms after the withdrawal of initial pharmacologic therapy.

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Combination drug therapy is not justified in most patients with GERD.
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In most patients with mild symptoms, antacids or over-the-counter H2-receptor blockers can be used as needed to help control symptoms. The lowest effective scheduled dosage of an H2-receptor blocker or a prokinetic agent should be used in patients with nonerosive esophagitis and moderate to severe symptoms.

Patients with erosive esophagitis or complicated disease should be given one of the proton pump inhibitors because of the higher rates of remission associated with these agents.22,24-26 The lowest effective dosage should be used to maintain remission.

Stage V: Surgery
Surgery may be considered in patients who fail medical therapy or develop complications of GERD.28 Patients can fail medical therapy because of noncompliance, inability to afford medications, relapse of symptoms soon after medication is stopped or relapse of symptoms despite continuous use of medication. Possible complicating factors include large hiatal hernia, Barrett's esophagus, severe esophagitis, recurrent esophageal strictures and severe pulmonary symptoms.28

Surgical intervention has been shown to provide long-term relief of symptoms in patients with GERD.9 The open Nissen fundoplication procedure has a cure rate of up to 90 percent. This operation can now be performed laparoscopically.6

Compared with an open procedure, the Nissen laparoscopic procedure has a similar success rate, but it can be performed in much less time (under two hours). With laparoscopic treatment, patients experience less pain and have fewer complications (e.g., splenic injury, deep vein thrombosis, infection).28 Consequently, they have a shorter hospital stay and an earlier return to work.28 The Toupet partial fundoplication can also be performed laparoscopically. The purpose of the Toupet and Nissen fundoplication procedures is to reduce a hiatal hernia and restore the competence of the gastroesophageal junction by constructing a valve mechanism.6

Each year members of two different medical faculties develop articles for "Practical Therapeutics." This article is one in a series coordinated by the Department of Family Practice at the University of Kentucky College of Medicine, Lexington. Guest editors of the series are Bryan F. Yeager, Pharm.D., Thomas Armsey, M.D., and Samuel C. Matheny, M.D., M.P.H.

The Authors

is assistant professor and family practice residency director at the University of Kentucky College of Medicine, Lexington. Dr. Scott received his medical degree from Southern Illinois University School of Medicine, Springfield, and completed family practice residency training at Southern Illinois University, Decatur.

is assistant professor at the University of Kentucky Colleges of Pharmacy and Medicine, and ambulatory care specialist in the Department of Internal Medicine. Dr. Gelhot received her pharmacy degrees from the University of Cincinnati and completed a postdoctoral residency in pharmacy practice at the University of Kentucky.

Address correspondence to Aimee R. Gelhot, Pharm.D., University of Kentucky Medical Center, 800 Rose St., Room C-117, Lexington, KY 40536-0084. Reprints are not available from the authors.


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Copyright © 1999 by the American Academy of Family Physicians.
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