INTRODUCTION

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Background

Gastroesophageal reflux is a normal physiological phenomenon experienced intermittently by most people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or without associated esophageal mucosal injury (ie, esophagitis).

Pathophysiology

The physiological and anatomical factors that prevent the reflux of gastric juice from the stomach into the esophagus include the following:

• The lower esophageal sphincter (LES) must have a normal length and pressure and a normal number of episodes of transient relaxation (relaxation in the absence of swallowing).
• The gastroesophageal junction must be located in the abdomen so that the diaphragmatic crura can assist the action of the LES, thus functioning as an extrinsic sphincter. The presence of a hiatal hernia disrupts this synergistic action and can promote reflux.
• Esophageal clearance must be able to neutralize the acid refluxed through the LES. (Mechanical clearance is achieved with esophageal peristalsis. Chemical clearance is achieved with saliva.)
• The stomach must empty properly.

Abnormal gastroesophageal reflux is caused by the abnormalities of one or more of the following protective mechanisms:

• A functional (frequent transient LES relaxation) or mechanical (hypotensive LES) problem of the LES is the most common cause of GERD.
• Certain foods (eg, coffee, alcohol), medications (eg, calcium channel blockers, nitrates, beta-blockers), or hormones (eg, progesterone) can decrease the pressure of the LES.
• Obesity is a contributing factor in GERD, probably because of the increased intra-abdominal pressure.

From a therapeutic point of view, informing patients that gastric refluxate is made up not only of acid but also of duodenal contents (eg, bile, pancreatic secretions) is important.

Frequency

United States

Heartburn is a common problem in the United States and in the Western world. Approximately 7% of the population experience symptoms of heartburn daily. An abnormal esophageal exposure to gastric juice is probably present in 20-40% of this population, meaning 20-40% of the people who experience heartburn do indeed have GERD. In the remaining population, heartburn is probably due to other causes. Because many individuals control symptoms with over-the-counter medications and without consulting a physician, the condition is likely underreported.

Mortality/Morbidity

• In addition to the typical symptoms (eg, heartburn, regurgitation, dysphagia), abnormal reflux can cause atypical symptoms, such as coughing, chest pain, and wheezing. Additional atypical symptoms from abnormal reflux include damage to the lungs (eg, pneumonia, asthma, idiopathic pulmonary fibrosis), vocal cords (eg, laryngitis, cancer), ear (eg, otitis media), and teeth (eg, enamel decay).
• Approximately 50% of patients with gastric reflux develop esophagitis. Esophagitis is classified into the following 4 grades based on its severity:
• • Grade I - Erythema
  • Grade II - Linear nonconfluent erosions
  • Grade III - Circular confluent erosions
  • Grade IV - Stricture or Barrett esophagus (Barrett esophagus is thought to be caused by the chronic reflux of gastric juice into the esophagus. Barrett esophagus occurs when the squamous epithelium of the esophagus is replaced by the intestinal columnar epithelium. Barrett esophagus is present in 8-15% of patients with GERD and may progress to adenocarcinoma. See Esophageal Cancer.)

Race

• White males are at a greater risk for Barrett esophagus and adenocarcinoma than other populations.

Sex

• No sexual predilection exists. GERD is as common in men as in women.
• The male-to-female ratio for esophagitis is 2:1-3:1. The male-to-female ratio for Barrett esophagus is 10:1.

Age

• GERD occurs in all age groups.
• The prevalence of GERD increases in people older than 40 years.

CLINICAL

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History

GERD can cause typical (esophageal) symptoms or atypical (extraesophageal) symptoms. However, a diagnosis of GERD based on the presence of typical symptoms is correct in only 70% of patients.

• Typical (esophageal) symptoms include the following:
• • Heartburn is the most common typical symptom of GERD. Heartburn is felt as a retrosternal sensation of burning or discomfort that usually occurs after eating or when lying down or bending over.
  • Regurgitation is an effortless return of gastric and/or esophageal contents into the pharynx. Regurgitation can induce respiratory complications if gastric contents spill into the tracheobronchial tree.
  • Dysphagia occurs in approximately one third of patients because of a mechanical stricture or a functional problem (eg, nonobstructive dysphagia secondary to abnormal esophageal peristalsis). Patients with dysphagia experience a sensation that food is stuck, particularly in the retrosternal area.
• Atypical (extraesophageal) symptoms include the following:
• • Coughing and/or wheezing are respiratory symptoms resulting from the aspiration of gastric contents into the tracheobronchial tree or from the vagal reflex arc producing bronchoconstriction. Approximately 50% of patients who have GERD-induced asthma do not experience heartburn.
  • Hoarseness results from irritation of the vocal cords by gastric refluxate. Hoarseness is often experienced by patients in the morning.
  • Reflux is the most common cause of noncardiac chest pain, accounting for approximately 50% of cases. Patients can present to the emergency department with pain resembling a myocardial infarction. Reflux should be ruled out (using esophageal manometry and 24-h pH testing if necessary) once a cardiac cause for the chest pain has been excluded. Alternatively, a therapeutic trial of a high-dose proton pump inhibitor (PPI) can be tried.

Physical

Noncontributory

Causes

See Pathophysiology.

DIFFERENTIALS

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Other Problems to Be Considered

Some studies have shown that GERD is highly prevalent in patients who are morbidly obese and that a high body mass index (BMI) is a risk factor for the development of GERD.^{1, 2, 3, 4, 5, 6}

The mechanism by which a high BMI increases esophageal acid exposure is not completely understood. Increased intragastric pressure and gastroesophageal pressure gradient, incompetence of the LES, and increased frequency of transient LES relaxations may all play a role in the pathophysiology of the disease in patients who are morbidly obese.

To further support the hypothesis that obesity increases esophageal acid exposure is the documentation of a dose-response relationship between increased BMI and increased prevalence of GERD and its complications. Therefore, the pathophysiology of GERD in patients who are morbidly obese might differ from that of patients who are not obese. The therapeutic implication of such a premise is that the correction of reflux in patients who are morbidly obese might be better achieved with a procedure that first controls obesity.

WORKUP

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Lab Studies

• Laboratory tests are seldom useful in establishing a diagnosis of GERD.

Imaging Studies

• Barium esophagogram
• • Barium esophagogram is particularly important for patients who experience dysphagia.
  • Barium esophagogram can show the presence and location of a stricture and the presence and shape of a hiatal hernia.
• Esophagogastroduodenoscopy
• • Esophagogastroduodenoscopy (EGD) identifies the presence and severity of esophagitis and the possible presence of Barrett esophagus.
  • EGD also excludes the presence of other diseases (eg, peptic ulcer) that can present similarly to GERD.
  • Although EGD is frequently performed to help diagnose GERD, it is not the most cost-effective diagnostic study because esophagitis is present in only 50% of patients with GERD.

Other Tests

• Esophageal manometry
• • Esophageal manometry defines the function of the LES and the esophageal body (peristalsis).
  • Esophageal manometry is essential for correctly positioning the probe for the 24-hour pH monitoring.
• Ambulatory 24-hour pH monitoring
• • Ambulatory 24-hour pH monitoring is the criterion standard in establishing a diagnosis of GERD with a sensitivity of 96% and a specificity of 95%.
  • Ambulatory 24-hour pH monitoring quantifies the gastroesophageal reflux and allows a correlation between the symptoms of reflux and the episodes of reflux.
  • Patients with endoscopically confirmed esophagitis do not need pH monitoring to establish a diagnosis of GERD.
• Indications for esophageal manometry and prolonged pH monitoring include the following:
• • Persistence of symptoms while taking adequate antisecretory therapy, such as PPI therapy
  • Recurrence of symptoms after discontinuation of acid-reducing medications
  • Investigation of atypical symptoms, such as chest pain or asthma, in patients without esophagitis
  • Confirmation of the diagnosis in preparation for antireflux surgery
• Radionuclide measurement of gastric emptying
• • Although delayed gastric emptying is present in as many as 60% of patients with GERD, this emptying is usually a minor factor in the pathogenesis of the disease in most patients (except in patients with advanced diabetes mellitus or connective tissue disorders).
  • Patients with delayed gastric emptying typically experience postprandial bloating and fullness in addition to other symptoms.

TREATMENT

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Medical Care

Treatment is a stepwise approach. The goals are to control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or other complications. The treatment is based on lifestyle modification and control of gastric acid secretion.

• Lifestyle modifications include the following:  
• • Losing weight (if overweight)
  • Avoiding alcohol, chocolate, citrus juice, and tomato-based products
  • Avoiding large meals
  • Waiting 3 hours after a meal before lying down
  • Elevating the head of the bed 8 inches
• Pharmacologic therapy  
• • Antacids were the standard treatment in the 1970s and are still effective in controlling mild symptoms of GERD. Antacids should be taken after each meal and at bedtime.
  • Histamine H2 receptor antagonists are the first line agents for patients with mild-to-moderate symptoms and grades I-II esophagitis. Histamine H2 receptor antagonists are effective for healing only mild esophagitis in 70-80% of patients with GERD and for providing maintenance therapy to prevent relapse. Tachyphylaxis has been observed, suggesting that pharmacologic tolerance can reduce the long-term efficacy of these drugs.
  • Additional H2 blocker therapy has been reported to be useful in patients with severe disease (particularly those with Barrett esophagus) who have nocturnal acid breakthrough.
  • PPIs are the most powerful medications available. They should be used only when GERD has been objectively documented. PPIs work by blocking the final step in the H+ ion secretion by the parietal cell. They have few adverse effects and are well tolerated for long-term use. However, recent data have shown that PPIs can interfere with calcium homeostasis and aggravate cardiac conduction defects. They have also been responsible for hip fracture in postmenopausal women.⁷
  • Prokinetic agents improve the motility of the esophagus and stomach. These agents are somewhat effective but only in patients with mild symptoms; other patients usually require additional acid-suppressing medications, such as PPIs. Long-term use of prokinetic agents may have serious, even potentially fatal, complications and should be discouraged.

Surgical Care

Approximately 80% of patients have a recurrent but nonprogressive form of GERD that is controlled with medications. Identifying the 20% of patients who have a progressive form of the disease is important because they may develop severe complications, such as strictures or Barrett esophagus. For patients who develop complications, surgical treatment should be considered at an earlier stage to avoid the sequelae of the disease that can have serious consequences.

• Indications for fundoplication include the following:  
• • Patients with symptoms that are not completely controlled by PPI therapy can be considered for surgery. Surgery can also be considered in patients with well-controlled disease who desire definitive, one-time treatment.
  • The presence of Barrett esophagus is an indication for surgery. Whether acid suppression improves the outcome or prevents the progression of Barrett esophagus remains unknown, but most authorities recommend complete acid suppression in patients with histologically proven Barrett esophagus.
  • The presence of extraesophageal manifestations of GERD may indicate the need for surgery. These include the following: (1) respiratory manifestations (eg, cough, wheezing, aspiration); (2) ear, nose, and throat manifestations (eg, hoarseness, sore throat, otitis media); and (3) dental manifestations (eg, enamel erosion).
  • Young patients
  • Poor patient compliance to medications
  • Postmenopausal women with osteoporosis
  • Patients with cardiac conduction defects
  • Cost of medical therapy
• Laparoscopic fundoplication  
• • Laparoscopic fundoplication is performed under general endotracheal anesthesia. Five small (5- to 10-mm) incisions are used. The fundus of the stomach is wrapped around the esophagus to create a new valve at the level of the gastroesophageal junction.
  • The essential elements of the operation are as follows:
  • • Complete mobilization of the fundus of the stomach with division of the short gastric vessels
    • Reduction of the hiatal hernia
    • Narrowing of the esophageal hiatus
    • Creation of a 360° fundoplication over a large intraesophageal dilator (Nissen fundoplication)
  • Laparoscopic fundoplication lasts 2-2.5 hours. The hospital stay is approximately 2 days. Patients resume regular activities within 2-3 weeks.
  • Approximately 92% of patients obtain resolution of symptoms after undergoing laparoscopic fundoplication.
• Several randomized clinical trials challenged the benefits of surgery in controlling GERD.  
• • In 2001, Lundell followed up his cohort of patients for 5 years and did not find surgery to be superior to PPI therapy.⁸
  • In 2001, Spechler found that, at 10 years after surgery, 62% of patients were back on antireflux medications.⁹
  • A very rigorous, randomized study by Anvari published in late 2006 reestablished surgery as the criterion standard in treating GERD.¹⁰ Anvari showed that, at 1 year, the outcome and the symptom control in the surgical group was better than that in the medical group.¹⁰
• Long-term results of laparoscopic antireflux surgery have shown that, at 10 years, 90% of patients are symptom free, and only a minority still takes PPIs.¹¹ 

MEDICATION

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The goals of pharmacotherapy are to prevent complications and to reduce morbidity.

Drug Category: H2 receptor antagonists

These agents are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. Although IV administration of H2 blockers may be used to treat acute complications (eg, GI bleeding), the benefits are not yet proven.

Drug Name	Cimetidine (Tagamet)
Description	Inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
Adult Dose	400 mg PO bid (800 mg bid or 400 mg PO qid)
Pediatric Dose	Not established Suggested dose is 1-2 mg/kg/d PO/IV divided q6h; not to exceed 40 mg/d
Contraindications	Documented hypersensitivity
Interactions	Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin, quinidine, propranolol, metronidazole, procainamide, and lidocaine
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Elderly people may experience confusional states; may cause impotence and gynecomastia in young males; may increase levels of many drugs; adjust dose or discontinue treatment if changes in renal function occur

Drug Name	Famotidine (Pepcid)
Description	Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
Adult Dose	20 mg PO bid (40 mg bid)
Pediatric Dose	Not established; 1-2 mg/kg/d PO/IV divided q6h suggested; not to exceed 40 mg/dose
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	If changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Drug Name	Nizatidine (Axid)
Description	Competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations.
Adult Dose	150 mg PO bid (300 mg PO qhs)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment

Drug Category: Proton pump inhibitors

These agents inhibit gastric acid secretion by inhibition of the H⁺/K⁺ ATPase enzyme system in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients not responding to H2 receptor antagonist therapy.

Drug Name	Lansoprazole (Prevacid)
Description	Inhibits gastric acid secretion. Used for up to 8 wk to treat all grades of erosive esophagitis.
Adult Dose	15-60 mg PO qd or 15 mg bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may increase theophylline clearance
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Consider adjusting dose in liver impairment

Drug Name	Rabeprazole (Aciphex)
Description	For short-term (4- to 8-wk) treatment and relief of symptomatic erosive or ulcerative GERD. In patients not healed after 8 wk, consider additional 8-wk course.
Adult Dose	20 mg PO qd for 4-8 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Symptomatic response does not exclude possibility of malignancy

Drug Name	Esomeprazole (Nexium)
Description	S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+ ATPase enzyme system at secretory surface of gastric parietal cells.
Adult Dose	20-40 mg PO qd for 4-8 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Symptomatic relief with proton pump inhibitors may mask symptoms of gastric malignancy

Drug Category: Prokinetics

These agents increase LES pressure to help reduce reflux of gastric contents. They also accelerate gastric emptying.

FOLLOW-UP

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Complications

• Esophagitis (esophageal mucosal damage) occurs in approximately 50% of patients.
• Barrett esophagus is one of the most serious complications of GERD because it may progress to cancer. Even though a prospective randomized trial has never been performed to compare PPIs to laparoscopic fundoplication, the authors believe fundoplication is preferable for the following reasons:  
• • PPIs, although effective in controlling the acid component of the refluxate, do not eliminate the reflux of bile, which some believe to be a major contributor to the pathogenesis of Barrett epithelium.
  • Patients with Barrett esophagus tend to have lower LES pressure and worse esophageal peristalsis than patients without Barrett esophagus. Patients with Barrett esophagus are also exposed to a larger amount of reflux.
  • A fundoplication offers the only possibility of stopping any kind of reflux by creating a competent LES. However, until the definitive answer is known, the authors recommend that patients with Barrett esophagus continue to undergo periodic endoscopic surveillance even after laparoscopic fundoplication.
• Respiratory complications include pneumonia, asthma, and interstitial lung fibrosis.

Prognosis

• Most patients with GERD do well with medications, although a relapse after cessation of medical therapy is common and indicates the need for long-term maintenance therapy.
• Identifying the subgroup of patients who may develop the most serious complications of the disease and treating them aggressively is important. Surgery at an early stage is most likely indicated in these patients.
• After a laparoscopic Nissen fundoplication, symptoms resolve in approximately 92% of patients.

Patient Education

• For excellent patient education resources, visit eMedicine's Heartburn/GERD/Reflux Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Reflux Disease (GERD), Heartburn, and Understanding Heartburn/GERD Medications.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Esophageal manometry and pH monitoring are considered essential before performing an antireflux operation. Endoscopy reveals that 50% of patients do not have esophagitis. The only way to determine if abnormal reflux is present and if symptoms are actually caused by gastroesophageal reflux is through pH monitoring.
• Achalasia can present with heartburn. Only esophageal manometry and pH monitoring can be used to distinguish achalasia from GERD. Therapy is completely different for the two conditions.

MULTIMEDIA

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Media file 1:  Esophagogastroduodenoscopy indicating Barrett esophagus.
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Media file 2:  Gastroesophageal reflux disease (GERD)/Barrett esophagus/adenocarcinoma sequence.
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Media file 3:  Barium swallow indicating hiatal hernia.
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Media file 4:  Ambulatory pH monitoring indicating episodes of reflux correlating with the heartburn experienced by the patient.
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Media file 5:  Laparoscopic Nissen fundoplication.
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REFERENCES

Section 11 of 11

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Article Last Updated: Mar 17, 2008