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Thomas G. Zimmerman, DO, FACOFP, South Nassau Family Medicine, 196 Merrick Road, Oceanside, NY 11572-1420.

E-mail address: tzimmerman@snch.org.

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Gastroesophageal reflux disease (GERD) is a common problem that occurs in both adult and pediatric populations in the United States (US). The economic impact of GERD is enormous; typical GERD therapy costs approximate $10 bil- lion per annum in the (US).1 GERD is referred to as “heart- burn” because the most common symptom is a substernal burning discomfort.2 GERD refers to the retrograde passage of gastric contents into the esophagus. It is believed that transient lower esophageal sphincter relaxations are a major cause for reflux. Untreated GERD can lead to dysplasia of the esopha- geal mucosa (known as Barrett’s esophagus [BE]3) and sub- sequent esophageal adenocarcinoma. Because the rate of ade- nocarcinoma has increased dramatically over the last 20 to 30 years, 4 it is extremely important for physicians to properly evaluate and manage GERD. Table 1 outlines some key points of information for readers to consider.

Epidemiology

Although GERD has been classically thought of as primar- ily a disease of the Western cultures, the number of cases has grown in the Eastern countries with the spread of the Western diet and lifestyle. Prevalence of heartburn is 8% in Italy, 10% in Japan, 17% in Canada, and 20 to 25% in the (US).5 More than 60 million adult Americans suffer from heartburn at least once a month and more than 25 million experience heartburn daily.6 A recent study in the US re- vealed that nearly 35% of all subjects experienced GERD symptoms, with the highest rates (50%) present in Hispanic populations.7 For patients with GERD symptoms, 40 to 60% or more have reflux esophagitis. GERD appears to be more prevalent in pregnant women8 and a higher compli- cation rate exists among the elderly.9 It is also common in pediatric populations. Complications of GERD are more frequent in white males and with increasing age. The prev- alence of heartburn increases dramatically after the age of 40 years. Obesity can also increase the likelihood of GERD by 300% or more.1‌‌

Table 1 Key points for GERD

  • Common in both adults and children; accounts for $10 billion in medical costs per year in the US

  • Usually presents as heartburn, but also as a cough, dysphagia, or hoarse voice

  • Can significantly affect patients’ quality of life, as well as lead to serious complications such as esophageal erosions, dysplasia, and cancer

  • Weight loss—progressive reduction in weight may lower abdominal pressure, which in turn leads to decrease in esophageal reflux

  • Although an empiric trial of proton-pump inhibitor therapy can be used in many patients, endoscopic examination is suggested in patients with recurrent or intractable symptoms

‌Pathophysiology

‌Most patients with GERD actually have normal baseline lower esophageal sphincter (LES) tone. The most common mechanism for acid reflux is transient relaxation of the LES (~90% of reflux episodes in normal subjects and 75% of episodes in patients with symptomatic GERD).10 Other mechanisms include breaching the LES as a result of in- creased intra-abdominal pressure (strain-induced reflux) and a baseline low LES pressure. The latter two mechanisms increase in frequency with greater reflux severity. Other factors include delayed gastric emptying (cofactor in 20% of GERD patients), medication use (particularly calcium- channel blockers), hiatal hernia (increased strain-induced reflux and poor acid clearance from hernia sac), and poor esophageal acid clearance (esophageal dysmotility, sclero- derma, decreased salivary production).11

Clinical presentation

Table 2 Warning signs of complicated GERD

  • Dysphagia

  • Odynophagia

  • Anemia (especially iron deficiency)

  • Bleeding (upper or lower GI)

  • Weight loss

  • Early satiety

Patients typically complain of a burning sensation in the chest, vomiting, acidic taste in the mouth, and regurgitation. Often, heartburn may wake patients at night. Some atypical symptoms include anginalike chest pain, dysphagia, hoarse- ness, and chronic cough. Many times, children with “silent” GERD may present with chronic cough and asthma symp- toms as opposed to actual heartburn.12

GERD may mimic peptic ulcer disease, infectious and toxic esophagitis, dyspepsia, chronic gallbladder disease, esophageal motility disorders, chronic pancreatitis, and ir- ritable bowel syndrome (IBS). The differential diagnosis should always include angina, especially in patients with known coronary artery disease or its risk factors, as well as diabetes mellitus.1

With the availability of H2 receptor blockers and, more recently, proton pump inhibitors (PPIs), it is ever more impor- tant for the astute clinician to ask all patients about the occur- rence of reflux symptoms. Patients self-medicating with over- the-counter (OTC) PPIs are likely to be largely symptom-free and may not admit to symptoms unless directly questioned; this is of great concern if these patients go undiagnosed and are never properly evaluated, as discussed next.

Diagnostic strategies

History and physical examination

In general, patients with intermittent, typical symptoms do not require any diagnostic evaluation and may be treated empirically.13 Exceptions include patients with alarm symp- toms (Table 2) such as weight loss, bleeding, anemia, odynophagia, dysphagia, or symptoms that persist for more than six weeks despite appropriate treatment.14

A comprehensive physical examination should be per- formed. Epigastric tenderness may suggest peptic ulcer dis- ease, gastritis, or other disease processes more than GERD. A digital rectal examination and fecal occult blood test should be done to rule out gastrointestinal (GI) bleeding, and an electro- cardiogram should be done to identify any cardiac disease. One can also consider obtaining a complete blood count to identify any chronic blood loss.1 Microcytic anemia accompanied with iron deficiency (especially in men and postmenopausal or post- hysterectomy women) should undergo both upper and lower endoscopic examination to search for any hemorrhagic ulcers, BE, or GI malignancies.15

‌Empiric trial of therapy‌‌

Resolution of symptoms after a 14-day trial of PPIs has been suggested to be an accurate method of diagnosing GERD.13 One study by Hillman using decision analysis demonstrated that empiric omeprazole therapy could be expected on average to be $1800 less costly than that of ranitidine.16 Because the cost of omeprazole has fallen sig- nificantly since this study was published in 1992, one can extrapolate even greater overall savings today. Most pa- tients can be diagnosed clinically with GERD by combining history and physical exam findings with response to PPIs.

Upper GI series

An upper GI (UGI) or barium swallow is an radiographic examination of the esophagus and stomach. This imaging study is helpful to ascertain any anatomical disorders or complications of GERD.17 A patient who has fasted over- night is given a barium “shake” to drink, which coats the digestive tract so it becomes more visible on the film. Movement of barium is observed while the patient is in different positions (Fig. 1). Barium swallowing can detect esophageal strictures and is also a reliable test for patients with dysphagia with an increase in sensitivity compared to esophagogastroduodenoscopy (EGD). Barium swallowing, however, is not sensitive enough to detect mucosal lesions such as esophagitis, and it often misses actual reflux as well.18,19

Esophagogastroduodenoscopy

Esophagogastroduodenoscopy is the gold standard for diagnosis of GERD and its possible complications. It con- sists of an examination of the lining of the esophagus, stomach, and upper duodenum with a small camera (flexible endoscope) inserted down the throat during conscious se- dation. Studies suggest that empiric treatment of GERD with PPIs is more cost-effective than endoscopy, but EGD is much more sensitive at diagnosing mucosal injury (esophagitis) and/or dysplasia (BE).20 EGD should be re- served for patients with long-lasting heartburn, dysphagia, or signs of GI bleeding, especially after a specific trial of acid suppression therapy. It should be noted, however, that a recent course of a PPI will often make the erosive changes associated with significant GERD harder to visualize on EGD.21

Acidity/impedance pH monitoring

Twenty-four-hour pH monitoring has been used since the 1970s to help document the presence of gastric juices in the esophagus.21 Testing for the presence of gastric juices in the esophagus can be particularly useful in patients with symptoms of GERD but negative EGD findings.22 Tradi- tionally, a wired antimony electrode is inserted transnasally into the esophagus and positioned about 5 cm above the superior margin of the lower esophageal sphincter.18 The total percentage time of esophageal pH below 4.0 is con- sidered to be the most useful outcome measure.1,23 There is also a wireless Bravo (Medtronic, Inc., Minneapolis, MN) pH-monitoring system that has been recently developed that allows 48-hour pH monitoring without using the transnasal catheter that some patients find intolerable.24 Figure 2 shows the capsule and a sample report. This system is preferred for patients who cannot tolerate the catheter, and studies suggest that the data it provides are comparable with the wired electrode systems.23 Unfortunately, many GERD patients will have normal pH studies because the refluxate causing the symptoms may be of neutral or slightly alkaline pH (especially patients taking PPIs). These findings also help explain why antacids, which can clearly neutralize the stomach’s acidic contents, are often ineffective in chronic GERD patients.23 Over the last 10 years, a new technique called ambulatory esophageal impedance–pH monitoring has been developed that can detect all types of gastroesoph- ageal reflux with higher sensitivity and specificity.25

Esophageal manometry

Esophageal manometry is most useful in the evaluation of patients with dysphagia or odynophagia. Manometry assesses peristalsis and contractile pressures in the body of the esophagus, in addition to measuring resting tone and relaxation of both the lower and upper esophageal sphinc- ters. Unfortunately, it is not as useful for the diagnosis of GERD because most subjects have normal findings. Its main purpose is for patients with dysphagia or achalasia, and in preoperative evaluation before antireflux surgery.26

Complications

GERD is a common chronic and relapsing condition that can result in serious complications for affected individuals. It is known that the productivity, quality of life, and overall well-being of individuals with GERD is compromised be- cause of heartburn, the hallmark of acid regurgitation. Many patients rate their quality of life to be lower than that reported by patients with untreated angina pectoris or chronic heart failure. Nocturnal episodes of acid reflux can severely affect a patient’s quality of life, resulting in ongo- ing daytime somnolence and irritability.27

A significant number of patients (especially pediatric patients12) may present with purely extra-esophageal symp- toms such as hoarse voice,28 cough, and wheezing. These patients may be diagnosed primarily with asthma, when indeed the precipitating factor is GERD.29 Studies have shown significant improvement in “asthma” in response to PPI treatment.30

Chronic, repeated exposure of the esophagus to acidic refluxates can lead to the development of esophagitis, an inflammation of esophageal mucosa, whose characteristics are hyperemia, presence of inflammatory cells, and basal zone hyperplasia. When endoscopy reveals actual mucosal damage such as ulcerations, friability, and bleeding, the diagnosis of erosive esophagitis is made.11 Chronic erosive esophagitis can cause the normal distal squamous epithe- lium to transform into a dysplastic columnar epithelium known as Barrett’s esophagus. BE can be recognized as a red mucosa located between the smooth, pale-pink esopha- geal squamous and the light-brown gastric mucosa. Its ex- istence may be characterized as tongues or patches extend- ing up from the gastroesophageal junction. Patients with BE (especially segments longer than 2-3 cm) should be moni- tored closely with serial EGDs to watch for the development of adenocarcinoma (in which the rate of development is 30-125 times the risk as that of the general population).11

Treatment

The main objectives of GERD treatment are to reduce or eliminate symptoms, improve quality of life, and reduce or prevent complications. It is extremely important to have continued follow-up with these patients to ensure that they are appropriately treated and, if necessary, re-evaluated over time.31‌

Table 3 Lifestyle modifications for GERD

  • Head elevation—increasing bed head height by 6 inches may lower abdominal pressure as well as distal esophageal acid exposure

  • Avoid foods that may reduce LES tone— chocolate, peppermint, spicy and acidic foods (pizza, tomatoes), cruciferous vegetables (cabbage, onions, cauliflower, Brussels sprouts, broccoli) and fatty foods

  • Avoid eating or drinking less than 3-4 hours before bedtime

  • More frequent, but smaller meals—may decrease acid production.

  • Weight loss—progressive reduction in weight may lower abdominal pressure, which in turn leads to decrease in esophageal reflux

  • Smoking cessation and minimal caffeine/alcohol consumption—all may lower LES pressure, resulting in incompetence of the LES

  • Avoid medication that decreases LES pressure such as muscle relaxants

  • Avoid tight clothing around the waist—tight clothing tends to increase abdominal pressure and promote gastroesophageal reflux

Lifestyle modifications

In our opinion, the foundation of treatment for all pa- tients with GERD should be comprehensive lifestyle mod- ifications. Table 3 shows the measures that have been tra- ditionally suggested. Meta-analysis of recommended lifestyle modifications has found that the measures directly related to the physical reflux of gastric contents (raising the head of the bed, weight loss) were effective and other more indirect measures (dietary restrictions, tobacco and alcohol avoid- ance) were statistically ineffective.32 However, because the reporting of GERD symptoms is itself very subjective, it would still be prudent to advocate all of these lifestyle modifications. In our clinical experience, we have encoun- tered many patients who were able to subjectively decrease the frequency and severity of GERD symptoms with these changes.

Medical treatments

Table 4 Histamine type-2 receptor blockers

Drug name

Typical Rx dosage

Cimetidine (Tagamet*) 400-800 mg twice

daily

Lowest monthly cost (generic)

$32

Ranitidine (Zantac*) Nizatidine (Axid*) Famotidine (Pepcid†)

150 mg twice daily 150 mg twice daily

$24

$52

20-40 mg twice daily $ 8

Over-the-counter antacids such as calcium carbonate, sodium bicarbonate, magnesium hydroxide, and aluminum hydroxide are used by many patients with varying, transient effectiveness. Alginic acid is an antirefluxant that, when combined with saliva, produces a foam thought to hinder the passage of acid from the stomach into the esophagus. Be- cause of their fast onset of action, these agents are best used for occasional symptoms. However, their therapeutic effects usually last only 30 to 60 minutes and are usually followed by a reflex increase in acid production by the stomach as they are cleared.33

Histamine type-2 receptors antagonists (H2Ras), are an- other class of agents that can serve as an appropriate, initial patient-directed therapy for mild to moderate GERD.34 All of the acid reducers in this class are about equally effective. The OTC dose of H2RAs is uniformly one half of the standard lowest original prescription dose for each com- pound. In general, most people with mild to moderate GERD symptoms who take acid reducers find improvement in their symptoms. Acid blockers have been used since the 1960s and are considered very safe; caution should be used, however, particularly with cimetidine, because of drug in- teractions associated with its inhibition of the cytochrome P450 system. A major weakness of the H2RAs as a class is the development of tachyphylaxis; after 30 days of use, their efficacy can decrease significantly. Table 4 lists the more commonly used H2RAs.1

Proton pump inhibitors have emerged as the treatment of choice for GERD because of their superior, continued ther- apeutic relief of symptoms.35 Based on several randomized, controlled trials, PPIs proved to be more effective than both H2RAs and placebo in controlling symptoms and in actual healing from erosive esophagitis over a four- to eight-week period. PPIs also are not associated with tachyphylaxis as are H2RAs.36 Although PPIs are, on average, initially much more expensive than antacids or H2RAs, their effectiveness at reducing complications has been well documented. Table 5 lists PPIs currently available in the US.37

Prokinetic agents such as metoclopramide have been periodically discussed in the literature as being able to increase LES tone and increase gastric emptying to reduce the occurrence of acid reflux. However, its use is limited because of undesirable central nervous system side effects such as restlessness and tremors.38

Table 5 Proton pump inhibitors

Drug name

omeprazole (Prilosec*) lansoprazole

(Prevacid†) pantoprazole (Protonix‡)

rabeprazole (Aciphex§)

esomeprazole (Nexium¶)

Omeprazole + sodium bicarbonate (ZegeridI)

Typical Rx dosage

20 mg QD to 40 mg BID 30 mg QD/BID

Lowest monthly cost

$ 18

$100

40 mg QD/BID

$110

20 mg QD/BID

$219

20 mg QD to 40 mg BID

$190

20-40 mg (omeprazole) QD

$ 24

Adapted from reference 36; prices estimated from drugstore.com.

*Procter & Gamble Co., Mason, OH.

†Novartis Intl AG, Basel, Switzerland.

‡Wyeth Pharmaceuticals, Madison, NJ.

§Eisai Co., Ltd., Tokyo, Japan.

AstraZeneca, plc., London, UK.

ISantarus, Inc., San Diego, CA.

degrees, whereas in the Toupet, it is 270 degrees. The wrap supports the LES muscle to help reduce transient LES relaxation and the subsequent flow of peptic juices from the stomach into the esophagus.39 Figure 3 illustrates the Nissen procedure.

The success rate for the laparoscopic procedure is 90 to 95% for patients who have the typical symptoms of GERD, such as heartburn, regurgitation, or belching. For patients with less typical symptoms, including hoarseness and chronic cough, the surgery is about 70 to 80% effective at relieving their symptoms. Although rare, the following complications and side effects may occur: injury to the esophagus, stomach, or spleen; bleeding, negligible symp- tom improvement; difficulty swallowing after surgery; loss of the ability to belch or vomit; and stomach bloating.1 The laparoscopic Nissen fundoplication offers less morbidity and mortality and shorter hospital stays (1-2 days) than the open procedure (4-7 days) with at least the same short-term outcome as the open procedure and better results compared with medical therapy.40 The mortality rate of the laparo- scopic Nissen fundoplication is 0.2%.1‌

Osteopathic manipulative treatment

Surgery

Surgical procedures are indicated for patients whose GERD symptoms are severe and/or nonresponsive medical treatments, including chronic esophagitis, BE, and pulmo- nary or laryngeal pathology secondary to recurrent reflux. Esophageal manometry must be done as part of the presur- gical evaluation to document the absence of any motility problems.1 The most common procedure performed is called fundoplication, of which there are two types: Nissen and Toupet. In these procedures, a new “valve” is con- structed as the upper portion of the stomach (fundus) is wrapped around the lower end of the esophagus and fixed (plication). The wrap in the Nissen procedure is a full 360

Because the etiologies of GERD are multifactorial (phys- ical reflux of acid, excess acid production, etc.), it is logical that there are various ways to treat it using osteopathic manipulative treatment (OMT). Although there has been a paucity of research on the effects of OMT on GERD, there are some studies demonstrating the clinical effectiveness of other types of manual manipulation.41 Although many GERD patients may still need concomitant medical treat- ment, OMT may well be able to reduce overall requirement for medicine, reduce health care costs, and improve pa- tients’ quality of life. There are many anecdotal reports of the effectiveness of OMT on GERD, some dating back more than 100 years.42

As a chronic condition, the gross musculoskeletal find- ings may reveal evidence of chronic change. The skin may feel cool or dry. The underlying musculature may be con- tractured and feel ropey. There will be a noticeable limita- tion of motion and tenderness over the transverse and spi- nous process of the involved vertebral segments. According to Kuchera, the sympathetic innervations of the upper GI tract are located at the T5-T11 vertebrae. Thus, patients with GERD are most likely to have facilitated segments and somatic dysfunctions in these areas.43 It is well documented that stimulation of the autonomic nervous system (which can occur with somatic dysfunction) can result in decreased motility of the stomach,44 which can exacerbate reflux into the esophagus. A common manipulative technique to nor- malize the sympathetic tone is rib raising45 to the T5-T9 appropriate rib segments for the esophagus and stomach.‌

An important factor that contributes to the competence of the gastroesophageal junction and LES is the action of the diaphragm. Thus, a pertinent aspect of manipulative treat- ment of the upper GI system is ensuring that the diaphragm is properly domed, whereby both sides are working sym- metrically during respiration.46

Stimulation of the vagus nerve activates and increases peristaltic action and secretion in the stomach glands. To reduce vagal activity to the stomach and esophagus, and relieve fascial tensions around the ganglion nodosum, the occipito-atlantal and atlanto-axial joints, and the suboccip- ital area can be treated with muscle energy47 and myofascial release techniques.48

Future directions

One promising therapeutic agent called lesogaberan is being studied by several researchers. It is a novel -y-aminobutyric acid type-B receptor agonist that acts to inhibit transient lower esophageal sphincter relaxation and reduced symp- tomatic episodes by 35% when used in conjunction with PPI treatment.49 Of course, further trials will be required to demonstrate this drug’s efficacy and safety profile.

Many endoscopic procedures involving plication and ab- lation have been developed over the past few years, with the promise of equivalent efficacy and decreased morbidity compared with laparoscopic or open procedures. Unfortu- nately, more research on the benefits vs risks of these procedures is needed before they can be approved for wide- spread use.50,51

Summary

Improvement in the quality of life of patients with GERD starts with the proper diagnosis and understanding the changes that occur secondary to GERD. The astute physi- cian must then implement rational interventions to alleviate the patient’s symptoms, prevent complications, and improve quality of life.

There has been considerable debate on whether medical or surgical treatment of GERD is most effective.52 What is clear, however, is that the final decision on which modality is used must be based on each patient’s individual circum- stances and needs.

References

  1. Cappell M: Clinical presentation, diagnosis, and management of gas- troesophageal reflux disease. Med Clin North Am 89:243-291, 2005

  2. Bozymski EM: Pathophysiology and diagnosis of gastroesophageal reflux disease. Am J Hosp Pharm 50(4 Suppl 1):4-6, 1993

  3. Barrett NR: Chronic peptic ulcer of the oesophagus and ‘oesophagitis.’

    Br J Surg 38:175-182, 1950

  4. Blot WJ, Devesa SS, Fraumeni JF Jr: Continuing climb in rates of esophageal adenocarcinoma: an update. JAMA 270:1320, 1993

  5. Minocha A: Gastroesphageal reflux disease. In: Handbook of Digestive Diseases. Thorofare, NJ: Slack Incorporated, 2004, 85-94

  6. Heidelbaugh J: Management of gastroesophageal reflux disease. Am Fam Physician 68:1311-1319, 2003

  7. Yuen E, Romney M, Toner RW, et al: Prevalence, knowledge and care patterns for gastro-oesophageal reflux disease in United States minor- ity populations. Aliment Pharmacol Ther 32:645-654, 2010

  8. Fill S, Malfertheiner M, Costa SD, et al: Handling of the gastroesoph- ageal reflux disease (GERD) during pregnancy—a review. Zeitschrift fur Geburtshilfe und Neonatologie 211:215-223, 2007

  9. Poh CH, Navarro-Rodriguez T, Fass R: Review: treatment of gastro- esophageal reflux disease in the elderly. Am J Med 123:496-501, 2010

  10. Mittal RK, Holloway RH, Penagini R, et al: Transient lower esopha- geal sphincter relaxation. Gastroenterology 109:601-610, 1995

  11. Goyal R: Diseases of the esophagus. In: Kasper DL, et al, eds. Har- rison’s Principles of Internal Medicine, 16th ed. New York, McGraw Hill, 2005, 1742-1743

  12. Thakkar K, Boatright RO, Gilger MA, et al: Gastroesophageal reflux and asthma in children: a systematic review. Pediatrics 125:e925-e930, 2010

  13. Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, et al: Omeprazole as a diagnostic tool in gastroesophageal reflux disease. Am J Gastroenterol 92:1997-2000, 1997

  14. DeVault K, Castell D: Updated guidelines for the diagnosis and treat- ment of gastroesophageal reflux disease. Am J Gastroenterol 100:190- 200, 2005

  15. Fireman Z, Zachlka R, Abu Mouch S, et al: The role of endoscopy in the evaluation of iron deficiency anemia in premenopausal women. Isr Med Assoc J 8:88-90, 2006

  16. Hillman AL, Bloom BS, Fendrick AM, et al: Cost and quality effects of alternative treatments for persistent gastroesophageal reflux disease. Arch Intern Med 152:1467-1472, 1992

  17. Dibble C, Levine MS, Rubesin SE, et al: Detection of reflux esoph- agitis on double-contrast esophagrams and endoscopy using the his- tologic findings as the gold standard. Abdom Imaging 29:421-425, 2004

  18. Lacy BE, Weiser K, Chertoff J, et al: The diagnosis of gastroesopha- geal reflux disease. Am J Med 123:583-592, 2010

  19. Ott DJ: Gastroesophageal reflux: what is the role of barium studies? AJR Am J Roentgenol 162:627-629, 1994

  20. Richter JE: Severe reflux esophagitis. Gastrointest Endosc Clin North Am 4:677-697, 1994

  21. Johnson LF, DeMeester TR: Twenty-four hour pH monitoring of the distal esophagus. A quantitative measure of gastroesophageal reflux. Am J Gastroenterol 62:325-332, 1974

  22. Pace F, Santalucia F, Bianchi Porro G, et al: Natural history of gastro-oesophageal reflux disease without esophagitis. Gut 32:845- 848, 1991


  23. ‌Pandolfino JE, Vela MF: Esophageal-reflux monitoring. Gastrointest Endosc 69:917-930, 2009

  24. Pandolfino JE, Schreiner MA, Lee TJ, et al: Bravo capsule placement in the gastric cardia: a novel method for analysis of proximal stomach acid environment. Am J Gastroenterol 100:1721-1727, 2005

  25. Sifrim D, Fornari F: Esophageal impedance-pH monitoring. Digest Liver Dis 40:161-166, 2008

  26. Pandolfino JE, Kahrilas PJ: AGA technical review: clinical use of esophageal manometry. Gastroenterology 128:209-224, 2005

  27. Gerson LB: Good night, sleep tight . . . and don’t let the acid bite! Gastroenterology 138:2551-2553, 2010

  28. Parsons JP, Benninger C, Hawley MP, et al: Vocal cord dysfunction: beyond severe asthma. Respir Med 104:504-509, 2010

  29. Moore JM, Vaezi MF: Extraesophageal manifestations of gastroesoph- ageal reflux disease: real or Imagined? Curr Opin Gastroenterol 26: 389-394, 2010

  30. Sopo SM, Radzik D, Calvani M: Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? A systematic review. J Investig Allergol Clin Immunol 19:1-5, 2009

  31. Nagahara A, Hojo M, Asaoka D, Watanabe S: Maintenance therapy of gastroesophageal reflux disease. Clin J Gastroenterol 3:61-68, 2010

  32. Kaltenbach T, Crockett S, Gerson LB: Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 166:965-971, 2006

  33. Weingart J, Ottenjann R: Calcium containing antacids and acid re- bound. Testing with intragastric titration and extragastric measurement of pH. Fortschr Med 95:1987-1989, 1977

  34. Van Pinxteren B, Numans ME, Bonis PA, et al: Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy- negative reflux disease. Cochrane Upper GI and Pancreatic Diseases Group. Cochrane Database Syst Rev 2001;4:CD002095.

  35. Heidelbaugh JJ, Nostrant TT: A cost-effective approach to the phar- macologic management of gastroesophageal reflux disease. Drug Ben- efit Trends 16:463-471, 2004

  36. Heidelbaugh JJ, Nostrant TT: Medical and surgical management of gastroesophageal reflux disease. Clin Fam Pract 6:547-568, 2004

  37. Haag S, Holtmann G: Onset of relief of symptoms of gastroesophageal reflux disease: post hoc analysis of two previously published studies comparing pantoprazole 20 mg once daily with nizatidine or ranitidine 150 mg twice daily. Clin Ther 32:678-690, 2010

  38. Robinson M: Prokinetic therapy for gastroesophageal reflux disease. Am Fam Physician 52:957-962, 965-966, 1995

  39. Richter JE: Gastroesophageal reflux disease. In: Yamada T, Alpers DH, Kaplowitz N, et al, eds. Textbook of Gastroenterology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003, 1196-1224

  40. Ruiz-Tovar J, Diez-Tabernilla M, Chames A, et al: Clinical outcome at 10 years after laparoscopic versus open Nissen fundoplication. J Lapa- roendosc Adv Surg Techniques 20:21-23, 2010

  41. Young MF, McCarthy PW, King SJ: Chiropractic manual intervention in chronic adult dyspepsia: a pilot study. Clin Chiropract 12:28-34, 2009

  42. Kelley ME: Diarrhea and acidity of the stomach. J Osteopath 6:33, 1899

  43. Kuchera M, Kuchera W: Osteopathic considerations in upper GI dis- orders. In: Osteopathic Considerations in Systemic Dysfunction, 2nd ed (rev). Toronto, Pearson Education Publishing, 1991, 89-93

  44. Willis W: The autonomic nervous system and its central control. In: Berne R, Levy M, eds. Physiology, 3rd ed. St. Louis, Mosby–Year Book, 1993, pp 245-252

  45. DiGiovanna E, Erner B, Dowling DJ: Articulatory and thrusting tech- niques for the ribs. In: DiGiovanna E, et al, eds. An Osteopathic Approach to Diagnosis and Treatment, 3rd ed, New York, Lippincott Williams & Wilkins, 2005, 396-397

  46. Comeaux Z: Diaphragmatic release. In Nelson K, ed. Somatic Dys- function in Osteopathic Family Medicine. New York, Lippincott Wil- liams & Wilkins, 2007, 253-243

  47. Ehrenfeuchter W, Sandhouse M: Muscle energy techniques. In Ward R, ed. Foundations for Osteopathic Medicine. 2nd ed. New York, Lippincott Williams & Wilkins, 2003, 888-890

  48. Essig-Beaty DR, Steele K, et al: Suboccipital inhibition. In: A Pocket Manual of OMT. New York, Lippincott Williams & Wilkins, 2006, p 226

  49. Boeckxstaens GE, Beaumont H, Mertens V, et al: Effects of lesogab- eran on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease. Gastroenterology 139:409-417, 2010

  50. Montgomery M, Håkanson B, Ljungqvist O, et al: Twelve months’ follow-up after treatment with the EndoCinch endoscopic technique for gastro-oesophageal reflux disease: a randomized, placebo-con- trolled study. Scand J Gastroenterol 41:1382-1389, 2006

  51. Bredenoord AJ: New therapies for gastroesophageal reflux disease. Minerva Gastroenterologica e Dietologica 56:129-138, 2010

  52. Romagnuolo J, Meier MA, Sadowski DC: Medical or surgical therapy for erosive reflux esophagitis: cost-utility analysis using a Markov model. Ann Surg 236:191-202, 2002