Scott Gabbard, MD

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

DIAGNOSTIC EVALUATION

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

CASE CONTINUED: NORMAL RESULTS ON TESTING

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

DIAGNOSTIC EVALUATION

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

CASE CONTINUED: NORMAL RESULTS ON TESTING

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

A 44-year-old woman presents with an 8-year history of intermittent heartburn, and in the past year she has been experiencing her symptoms daily. She says the heartburn is constant and is worse immediately after eating spicy or acidic foods. She says she has had no dysphagia, weight loss, or vomiting. Her symptoms have persisted despite taking a histamine (H)₂-receptor antagonist twice daily plus a proton pump inhibitor (PPI) before breakfast and dinner for more than 3 months.

She has undergone upper endoscopy 3 times in the past 8 years. Each time, the esophagus was normal with a regular Z-line and normal biopsy results from the proximal and distal esophagus.

The patient believes she has severe gastroesophageal reflux disease (GERD) and asks if she is a candidate for fundoplication surgery.

HEARTBURN IS A SYMPTOM; GERD IS A CONDITION

A distinction should be made between heartburn—the symptom of persistent retrosternal burning and discomfort—and gastroesophageal reflux disease—the condition in which reflux of stomach contents causes troublesome symptoms or complications.¹ While many clinicians initially diagnose patients who have heartburn as having GERD, there are many other potential causes of their symptoms.

For patients with persistent heartburn, an empiric trial of a once-daily PPI is usually effective, but one-third of patients continue to have heartburn.^2,3 The most common cause of this PPI-refractory heartburn is functional heartburn, a functional or hypersensitivity disorder of the esophagus.⁴

PATHOPHYSIOLOGY IS POORLY UNDERSTOOD

DIAGNOSTIC EVALUATION

Clinicians have several tests available for diagnosing these conditions.

Upper endoscopy

Upper endoscopy is recommended for patients with heartburn that does not respond to a 3-month trial of a PPI.⁹ Endoscopy is also indicated in any patient who has any of the following “alarm symptoms” that could be due to malignancy or peptic ulcer:

• Dysphagia
• Odynophagia
• Vomiting
• Unexplained weight loss or anemia
• Signs of gastrointestinal bleeding
• Anorexia
• New onset of dyspepsia in a patient over age 60.

During upper endoscopy, the esophagus is evaluated for reflux esophagitis, Barrett esophagus, and other inflammatory disorders such as infectious esophagitis. But even if the esophageal mucosa appears normal, the proximal and distal esophagus should be biopsied to rule out an inflammatory disorder such as eosinophilic or lymphocytic esophagitis.

If endoscopic and esophageal biopsy results are inconclusive, a workup for an esophageal motility disorder is the next step. Dysphagia is the most common symptom of these disorders, although the initial presenting symptom may be heartburn or regurgitation that persists despite PPI therapy.

Manometry is used to test for motility disorders such as achalasia and esophageal spasm.¹⁰ After applying a local anesthetic inside the nares, the clinician inserts a flexible catheter (about 4 mm in diameter) with 36 pressure sensors spaced at 1-cm intervals into the nares and passes it through the esophagus and lower esophageal sphincter. The patient then swallows liquid, and the sensors relay the esophageal response, creating a topographic plot that shows esophageal peristalsis and lower esophageal sphincter relaxation.

Achalasia is identified by incomplete lower esophageal sphincter relaxation combined with 100% failed peristalsis in the body of the esophagus. Esophageal spasms are identified by a shortened distal latency, which corresponds to premature contraction of the esophagus during peristalsis.¹¹

Esophageal pH testing

Measuring esophageal pH levels is an important step to quantify gastroesophageal reflux and determine if symptoms occur during reflux events. According to the updated Porto GERD consensus group recommendations,¹² a pH test is positive if the acid exposure time is greater than 6% of the testing period. Testing the pH differentiates between GERD (abnormal acid exposure), reflux hypersensitivity (normal acid exposure, strong correlation between symptoms and reflux events), and functional heartburn (normal acid exposure, negative correlation between reflux events and symptoms).⁵ For this test, a pH probe is placed in the esophagus transnasally or endoscopically. The probe records esophageal pH levels for 24 to 96 hours in an outpatient setting. Antisecretory therapy needs to be withheld for 7 to 10 days before the test.

Transnasal pH probe. For this approach, a thin catheter is inserted through the nares and advanced until the tip is 5 cm proximal to the lower esophageal sphincter. (The placement is guided by the results of esophageal manometry, which is done immediately before pH catheter placement.) The tube is secured with clear tape on the side of the patient’s face, and the end is connected to a portable recorder that compiles the data. The patient pushes a button on the recorder when experiencing heartburn symptoms. (A nurse instructs the patient on proper procedure.) After 24 hours, the patient either removes the catheter or has the clinic remove it. The pH and symptom data are downloaded and analyzed.

Transnasal pH testing can be combined with impedance measurement, which can detect nonacid reflux or weakly acid reflux. However, the clinical significance of this measurement is unclear, as multiple studies have found total acid exposure time to be a better predictor of response to therapy than weakly acid or nonacid reflux.¹²

Wireless pH probe. This method uses a disposable, catheter-free, capsule device to measure esophageal pH. The capsule, about the size of a gel capsule or pencil eraser, is attached to the patient’s esophageal lining, usually during upper endoscopy. The capsule records pH levels in the lower esophagus for 48 to 96 hours and transmits the data wirelessly to a receiver the patient wears. The patient pushes buttons on the receiver to record symptom-specific data when experiencing heartburn, chest pain, regurgitation, or cough. The capsule detaches from the esophagus spontaneously, generally within 7 days, and is passed out of the body through a bowel movement.

Diagnosing functional heartburn

CASE CONTINUED: NORMAL RESULTS ON TESTING

Based on these results, her condition is diagnosed as functional heartburn, consistent with the Rome IV criteria.⁵

Patient education is key

Patient education about the pathogenesis, natural history, and treatment options is the most important aspect of treating any functional gastrointestinal disorder. This includes the “brain-gut connection” and potential mechanisms of dysregulation. Patient education along with assessment of symptoms should be part of every visit, especially before discussing treatment options.

Patients whose condition is diagnosed as functional heartburn need reassurance that the condition is benign and, in particular, that the risk of progression to esophageal adenocarcinoma is minimal in the absence of Barrett esophagus.¹³ Also important to point out is that the disorder may spontaneously resolve: resolution rates of up to 40% have been reported for other functional gastrointestinal disorders.¹⁴

Antisecretory medications may work for some

A PPI or H₂-receptor antagonist is the most common first-line treatment for heartburn symptoms. Although most patients with functional heartburn experience no improvement in symptoms with an antisecretory agent, a small number report some relief, which suggests that acid-suppression therapy may have an indirect impact on pain modulation in the esophagus.¹⁵ In patients who report symptom relief with an antisecretory agent, we suggest continuing the medication tapered to the lowest effective dose, with repeated reassurance that the medication can be discontinued safely at any time.

Antireflux surgery should be avoided

Antireflux surgery should be avoided in patients with normal pH testing and no objective finding of reflux, as this is associated with worse subjective outcomes than in patients with abnormal pH test results.¹⁶

Neuromodulators

It is important to discuss with patients the concept of neuromodulation, including the fact that antidepressants are often used because of their effects on serotonin and norepinephrine, which decrease visceral hypersensitivity.

The selective serotonin reuptake inhibitor citalopram has been shown to reduce esophageal hypersensitivity,¹⁷ and a tricyclic antidepressant has been shown to improve quality of life.¹⁸ These results have led experts to recommend a trial of a low dose of either type of medication.¹⁹ The dose of tricyclic antidepressant often needs to be increased sequentially every 2 to 4 weeks.

Interestingly, melatonin 6 mg at bedtime has also shown efficacy for functional heartburn, potentially due to its antinociceptive properties.²⁰

Alternative and complementary therapies

Many esophageal centers use cognitive behavioral therapy and hypnotherapy as first-line treatment for functional esophageal disorders. Here again, it is important for the patient to understand the rationale of therapy for functional gastrointestinal disorders, given the stigma in the general population regarding psychotherapy.

Cognitive behavioral therapy has been used for functional gastrointestinal disorders for many years, as it has been shown to modulate visceral perception.²¹ Although published studies are limited, research regarding other functional esophageal disorders suggests that patients who commit to long-term behavioral therapy have had a significant improvement in symptoms.²²

The goal of esophageal-directed behavioral therapy is to promote focused relaxation using deep breathing techniques, which can help patients manage esophageal hypervigilance, especially if symptoms continue despite neuromodulator therapy. Specifically, hypnotherapy has been shown to modulate functional chest pain through the visceral sensory pathway and also to suppress gastric acid secretion.^21,23 A study of a 7-week hypnotherapy program reported significant benefits in heartburn relief and improved quality of life in patients with functional heartburn.²⁴ The data support the use of behavioral therapies as first-line therapy or as adjunctive therapy for patients already taking a neuromodulator.

CASE FOLLOW-UP: IMPROVEMENT WITH TREATMENT

During a follow-up visit, the patient is given several printed resources, including the Rome Foundation article on functional heartburn.⁵ We again emphasize the benign nature of functional heartburn, noting the minimal risk of progression to esophageal adenocarcinoma, as she had no evidence of Barrett esophagus on endoscopy. And we discuss the natural course of functional heartburn, including the spontaneous resolution rate of about 40%.

For treatment, we present her the rationale for using neuromodulators and reassure her that these medications are for treatment of visceral hypersensitivity, not for anxiety or depression. After the discussion, the patient opts to start amitriptyline therapy at 10 mg every night at bedtime, increasing the dose by 10 mg every 2 weeks until symptoms improve, up to 75–100 mg every day.

After 3 months, the patient reports a 90% improvement in symptoms while on amitriptyline 30 mg every night. She is also able to taper her antisecretory medications once symptoms are controlled. We plan to continue amitriptyline at the current dose for 6 to 12 months, then discuss a slow taper to see if her symptoms spontaneously resolve.

A 71-year-old man was referred to the gastroenterology department for evaluation of 9 months of progressive swallowing difficulties associated with epigastric and chest discomfort.

He was a previous smoker (17 pack-years), with a history of coronary artery disease, hypertension, and cervical spinal stenosis requiring decompressive laminectomy with a postoperative course complicated by episodes of aspiration.

DYSPHAGIA: OROPHARYNGEAL OR ESOPHAGEAL

Difficulty swallowing (dysphagia) can be caused by problems in the oropharynx or in the esophagus. Difficulty initiating a swallow can be thought of as oropharyngeal dysphagia, whereas the intermittent sensation of food stuck in the neck or chest is considered esophageal dysphagia.

Focused questioning can help differentiate oropharyngeal symptoms from esophageal symptoms. For example, difficulty clearing secretions or passing the food bolus beyond the mouth or frequent coughing spells while eating is consistent with oropharyngeal dysphagia and suggests a neurologic cause. Our patient, however, presented with a constellation of symptoms more suggestive of esophageal dysphagia.

When eliciting a history of esophageal symptoms, it is crucial to determine the progression of swallowing difficulty, as well as how it directly relates to eating solids or liquids, or both. Difficulty swallowing solid foods that has progressed over time to include liquids would raise concern for an obstruction such as a stricture, ring, or malignancy. On the other hand, abrupt onset of intermittent dysphagia to both solids and liquids would raise concern for a motility disorder of the esophagus. This patient presented with an abrupt onset of intermittent symptoms to both solids and liquids that was associated with substernal chest pain.

Once coronary disease was ruled out by cardiac biomarker testing, electrocardiography, and a pharmacologic stress test, our patient underwent upper endoscopy, which showed a normal esophageal mucosa without masses or obstruction and no evidence of peptic ulcer disease.

WHAT IS THE NEXT STEP?

When upper endoscopy is negative and cardiac causes and gastroesophageal reflux disease have been ruled out, an esophageal motility disorder should be considered.

1. After obstruction has been ruled out with upper endoscopy, which should be the next step in the investigation of esophageal dysphagia?

• A 24-hour pH recording
• Barium esophagography
• Modified barium swallow
• Computed tomography of the chest

Barium esophagography is the optimal fluoroscopic study to evaluate the esophageal phase of the swallow. This study requires the patient to swallow a thick barium solution and a 13-mm barium pill under video analysis. It is useful early in the investigation of esophageal dysphagia because it can potentially reveal areas of esophageal luminal narrowing not detected endoscopically, as well as detail the rate of esophageal emptying.¹

The modified barium swallow, which is performed with the assistance of a speech pathologist, is similar but only shows the oropharynx as far as the cervical esophagus. Therefore, it would be the best fluoroscopic test to assess patients with possible aspiration or oropharyngeal dysphagia, whereas barium esophagography would be the test of choice in evaluating esophageal dysmotility or mechanical obstruction.

pH testing may be helpful in diagnosing gastroesophageal reflux disease but is less helpful in the evaluation of dysphagia.

Computed tomography of the chest may be useful to evaluate for extrinsic compression of the esophagus, but it is not the best next step in the evaluation of dysphagia.

Our patient underwent barium esophagography, which revealed tertiary contractions in the mid and distal esophagus with slight narrowing of the lower cervical esophagus (Figure 1). (Primary contractions are elicited when initiating a swallow that propels the food bolus through the esophagus, while secondary contractions follow in response to esophageal distention to move all remaining esophageal contents from the thoracic esophagus. Tertiary contractions are abnormal, nonpropulsive, spontaneous contractions of the esophageal body that are initiated without swallowing.²)

EOSINOPHILIC ESOPHAGITIS

Histologic study of biopsies of the mid and distal esophagus from our patient’s upper endoscopy revealed 5 eosinophils per high-power field.

2. Does this patient meet the criteria for the diagnosis of eosinophilic esophagitis?

• Yes
• No

No. Having eosinophils in the esophagus is not enough to diagnose eosinophilic esophagitis, as eosinophils are also common in patients with gastroesophageal reflux disease.

Eosinophilic esophagitis is defined as a chronic immune-mediated esophageal disease with histologically eosinophil-predominant inflammation (with more than 15 eosinophils per high-power field). The diagnosis is additionally based on symptoms and endoscopic appearance.³ When investigating possible eosinophilic esophagitis, it is recommended that 2 to 4 samples be obtained from at least 2 different locations in the esophagus (eg, proximal and distal), because the inflammatory changes can be patchy.

3. What is the likely cause of this patient’s dysphagia?

• Eosinophilic esophagitis
• Achalasia
• Esophageal spasm
• Extrinsic compression
• Esophageal malignancy

Eosinophilic esophagitis causes characteristic symptoms that include difficulty swallowing, chest pain that does not respond to antisecretory therapy, and regurgitation of undigested food. As we discussed above, this patient has only 5 eosinophils per high-power field and does not meet the histologic criteria for eosinophilic esophagitis.

Achalasia has a characteristic “bird’s beak” appearance on esophagography that results from distal tapering of the esophagus to the gastroesophageal junction,¹ and this is not apparent on our patient’s study.

Review of this patient’s esophagogram also does not reveal any extrinsic compression, esophageal malignancy, or distal tapering suggesting achalasia. In light of the abrupt onset of symptoms related to both solids and liquids associated with atypical chest pain, the primary concern should be for esophageal spasm.

ONE MORE TEST

4. What study would you order next to better elucidate the cause of this patient’s esophageal disorder?

• High-resolution esophageal manometry
• Esophagogastroduodenoscopy (EGD) with endoscopic ultrasonography
• 24-hour pH and impedance testing
• Wireless motility capsule

Esophageal manometry (Figure 2) is used to evaluate the function and coordination of the muscles of the esophagus, as in disorders of esophageal motility.

High-resolution manometry is the gold standard for evaluation of esophageal motility. It is appropriate in evaluating dysphagia or noncardiac chest pain without evidence of mechanical obstruction, ulceration, or inflammation.^4,5

High-resolution manometry differs from conventional manometry in that the catheter has more sensors to measure intraluminal pressure (36 rather than the usual 7 to 12). The data are translated into pressure topography plots (Figure 3).^6,7

Updated guidelines on how to interpret the findings of high-resolution manometry are known as the Chicago 3.0 criteria.⁴ According to this system, esophageal motility disorders are grouped on the basis of lower esophageal sphincter relaxation and then further subdivided based on the character of peristalsis.

EGD with endoscopic ultrasonography would not be appropriate at this time because there is little suspicion of an extraluminal mass that needs to be investigated.

A 24-hour pH and impedance study is helpful in determining the presence of esophageal acid exposure in patients presenting with gastroesophageal reflux disease. This patient does not have symptoms of heartburn or regurgitation; therefore, this investigation would not be of value.

A wireless motility capsule would help in investigating gastric and small-bowel motility and may be useful in the future for this patient, but at this point it would provide little additional utility.

ESOPHAGEAL SPASM

Our patient underwent high-resolution esophageal manometry. The results (Figure 4) revealed a normal resting pressure in the lower esophageal sphincter and complete relaxation in all swallows. The body of the esophagus demonstrated premature contractions in 90% of swallows. Overall, these findings were consistent with the diagnosis of distal esophageal spasm.

In addition to incorporating data obtained from endoscopy, esophagography, and manometry, it is crucial to identify the patient’s predominant symptom when planning treatment. For example, is the prevailing symptom dysphagia or chest pain? Additional consideration must be given to medical, surgical, and psychiatric comorbidities.

5. Which of the following is appropriate medical therapy for esophageal spasm?

• Calcium channel blockers
• Nitrates
• Hydralazine
• Phosphodiesterase 5 (PDE5) inhibitors
• All of the above

All of these have been used to treat distal esophageal spasm as well as other hypercontractile esophageal motility disorders.^8–20

Calcium channel blockers have proven to be effective in randomized controlled trials. Diltiazem has been shown to be beneficial at doses ranging from 60 to 90 mg, as has nifedipine 10 to 20 mg 3 times daily. Although different drugs of this class tend to relax the lower esophageal sphincter to different degrees, when choosing among them in patients with hypercontractile disorders there is little concern for potentially precipitating reflux.^8–13

Nitrates, hydralazine, and PDE5 inhibitors have been effective in uncontrolled studies but have not been studied in randomized trials.^14–17

Other treatments. Patients may also benefit from neuromodulators such as trazodone and imipramine for chest pain and optimization of antisecretory therapy if they have concomitant gastroesophageal reflux disease.^18–20

Patients who have documented esophageal hypercontractility along with reflux disease confirmed by an abnormal pH study show significant improvement in their chest pain symptoms with high doses of a proton pump inhibitor (PPI). As our patient presented with chest pain and dysphagia, a dedicated pH study was not needed, and we could progress straight to manometry and a trial of a PPI.

Our patient was started on a PPI and nifedipine but developed a pruritic rash. As rash does not preclude using another medication in the same class, his treatment was changed to diltiazem 30 mg by mouth 3 times a day, and his dysphagia improved. However, he continued to experience intermittent chest pain with swallowing. After discussion of neuromodulator therapy, he declined additional pharmacologic therapy.

A NONPHARMACOLOGIC TREATMENT?

6. Which of the following would you offer this patient as a nonpharmacologic alternative for his esophageal pain?

• St. John’s wort
• Ginkgo biloba
• Ginseng
• Peppermint extract
• Eucalyptus oil

In a small, open-label study in patients with esophageal spasm, the use of 5 drops of commercially available 11% peppermint extract in 10 mL of water significantly decreased simultaneous contractions and resolved chest pain.²¹ Esophageal manometry was performed 10 minutes after the peppermint solution was consumed, and the results showed improvement in esophageal spasm. While the authors of this study did not make any formal recommendations, the findings suggest that peppermint extract should be given 10 minutes before meals.

There is no evidence for or against the use of the other nonpharmacologic treatments mentioned here.

PAIN RELIEF

7. If a pharmacologic approach were chosen, which would be the best option for pain relief in this patient?

• Oxycodone 5 mg every 8 hours
• Acetaminophen 650 mg every 8 hours
• Ibuprofen 400 mg every evening at bedtime
• Trazodone 100 mg every evening at bedtime
• Imipramine 50 mg every evening at bedtime
• Aripiprazole 5 mg by mouth every day

Trazodone would be the most appropriate of these options. Doses of 100 mg to 150 mg every evening at bedtime have been shown to significantly improve global assessment scores of pain at 6 weeks.¹⁸

Imipramine 50 mg every evening at bedtime would be another option and also has been shown to reduce chest pain.¹⁹

Even though these were the doses that were investigated, in clinical practice it is common to start at lower doses (trazodone 50 mg or imipramine 10 mg) and to then titrate every 4 weeks based on the patient’s response.

Opiates (eg, oxycodone) should be avoided, as they can cause esophageal motility disorders such as spasm or achalasia.²²

Acetaminophen and aripiprazole have not been studied exclusively for their effect on chest pain related to esophageal spasm.

RECURRENT SYMPTOMS

The patient’s dysphagia initially decreased while he was taking diltiazem 30 mg 3 times a day, but it recurred after 6 months. The dosage was increased to 60 mg 3 times a day over the course of the next year, with minimal response. (The maximum dose is 90 mg 4 times a day, but because of side effects of lightheadedness and dizziness, out patient could not tolerate more than 60 mg 3 times a day).

8. What endoscopic therapies are appropriate for patients with esophageal spasm that does not respond to medication?

• Bougie dilation
• Balloon dilation
• Onabotulinum toxin injection
• Expandable mesh stent placement
• Mucosal sclerotherapy

Onabotulinum toxin injections have been shown to improve dysphagia when given in a linear pattern.²³

Endoscopic dilation has not been shown to be beneficial in this setting, as a study found no difference in efficacy between therapeutic (54-French) and sham (24-French) bougie dilation.²⁴

Our patient received 100 units of onabotulinum toxin (10 units every centimeter in the distal 10 cm of the esophagus). Afterward, he experienced resolution of dysphagia, with only mild intermittent chest pain, which was controlled by taking peppermint extract as needed. The symptoms returned approximately 1 year later but responded to repeat endoscopy with onabotulinum toxin injections.^23,25

Peroral endoscopic myotomy

Another relatively new endoscopic treatment for esophageal motility disorders is peroral endoscopic myotomy (Figure 5). During this procedure a tiny incision is made in the esophageal mucosa, permitting the endoscope to tunnel within the lining. The smooth muscle of the distal esophagus and lower esophageal sphincter is then cut, thereby freeing either the spastic muscle (in distal esophageal spasm) or the hyperactive lower esophageal sphincter (in achalasia).^26,27

In an open trial, after undergoing peroral endoscopic myotomy for esophageal spasm and hypercontractile esophagus, 89% of patients had complete relief of dysphagia, and 92% had palliation of chest pain.²⁸ Of note, the rate of relief of dysphagia was higher for patients with achalasia (98%) than for nonachalasia patients (71%).

A 71-year-old man was referred to the gastroenterology department for evaluation of 9 months of progressive swallowing difficulties associated with epigastric and chest discomfort.

He was a previous smoker (17 pack-years), with a history of coronary artery disease, hypertension, and cervical spinal stenosis requiring decompressive laminectomy with a postoperative course complicated by episodes of aspiration.

DYSPHAGIA: OROPHARYNGEAL OR ESOPHAGEAL

Difficulty swallowing (dysphagia) can be caused by problems in the oropharynx or in the esophagus. Difficulty initiating a swallow can be thought of as oropharyngeal dysphagia, whereas the intermittent sensation of food stuck in the neck or chest is considered esophageal dysphagia.

Focused questioning can help differentiate oropharyngeal symptoms from esophageal symptoms. For example, difficulty clearing secretions or passing the food bolus beyond the mouth or frequent coughing spells while eating is consistent with oropharyngeal dysphagia and suggests a neurologic cause. Our patient, however, presented with a constellation of symptoms more suggestive of esophageal dysphagia.

When eliciting a history of esophageal symptoms, it is crucial to determine the progression of swallowing difficulty, as well as how it directly relates to eating solids or liquids, or both. Difficulty swallowing solid foods that has progressed over time to include liquids would raise concern for an obstruction such as a stricture, ring, or malignancy. On the other hand, abrupt onset of intermittent dysphagia to both solids and liquids would raise concern for a motility disorder of the esophagus. This patient presented with an abrupt onset of intermittent symptoms to both solids and liquids that was associated with substernal chest pain.

Once coronary disease was ruled out by cardiac biomarker testing, electrocardiography, and a pharmacologic stress test, our patient underwent upper endoscopy, which showed a normal esophageal mucosa without masses or obstruction and no evidence of peptic ulcer disease.

WHAT IS THE NEXT STEP?

When upper endoscopy is negative and cardiac causes and gastroesophageal reflux disease have been ruled out, an esophageal motility disorder should be considered.

1. After obstruction has been ruled out with upper endoscopy, which should be the next step in the investigation of esophageal dysphagia?

• A 24-hour pH recording
• Barium esophagography
• Modified barium swallow
• Computed tomography of the chest

Barium esophagography is the optimal fluoroscopic study to evaluate the esophageal phase of the swallow. This study requires the patient to swallow a thick barium solution and a 13-mm barium pill under video analysis. It is useful early in the investigation of esophageal dysphagia because it can potentially reveal areas of esophageal luminal narrowing not detected endoscopically, as well as detail the rate of esophageal emptying.¹

The modified barium swallow, which is performed with the assistance of a speech pathologist, is similar but only shows the oropharynx as far as the cervical esophagus. Therefore, it would be the best fluoroscopic test to assess patients with possible aspiration or oropharyngeal dysphagia, whereas barium esophagography would be the test of choice in evaluating esophageal dysmotility or mechanical obstruction.

pH testing may be helpful in diagnosing gastroesophageal reflux disease but is less helpful in the evaluation of dysphagia.

Computed tomography of the chest may be useful to evaluate for extrinsic compression of the esophagus, but it is not the best next step in the evaluation of dysphagia.

Our patient underwent barium esophagography, which revealed tertiary contractions in the mid and distal esophagus with slight narrowing of the lower cervical esophagus (Figure 1). (Primary contractions are elicited when initiating a swallow that propels the food bolus through the esophagus, while secondary contractions follow in response to esophageal distention to move all remaining esophageal contents from the thoracic esophagus. Tertiary contractions are abnormal, nonpropulsive, spontaneous contractions of the esophageal body that are initiated without swallowing.²)

EOSINOPHILIC ESOPHAGITIS

Histologic study of biopsies of the mid and distal esophagus from our patient’s upper endoscopy revealed 5 eosinophils per high-power field.

2. Does this patient meet the criteria for the diagnosis of eosinophilic esophagitis?

• Yes
• No

No. Having eosinophils in the esophagus is not enough to diagnose eosinophilic esophagitis, as eosinophils are also common in patients with gastroesophageal reflux disease.

Eosinophilic esophagitis is defined as a chronic immune-mediated esophageal disease with histologically eosinophil-predominant inflammation (with more than 15 eosinophils per high-power field). The diagnosis is additionally based on symptoms and endoscopic appearance.³ When investigating possible eosinophilic esophagitis, it is recommended that 2 to 4 samples be obtained from at least 2 different locations in the esophagus (eg, proximal and distal), because the inflammatory changes can be patchy.

3. What is the likely cause of this patient’s dysphagia?

• Eosinophilic esophagitis
• Achalasia
• Esophageal spasm
• Extrinsic compression
• Esophageal malignancy

Eosinophilic esophagitis causes characteristic symptoms that include difficulty swallowing, chest pain that does not respond to antisecretory therapy, and regurgitation of undigested food. As we discussed above, this patient has only 5 eosinophils per high-power field and does not meet the histologic criteria for eosinophilic esophagitis.

Achalasia has a characteristic “bird’s beak” appearance on esophagography that results from distal tapering of the esophagus to the gastroesophageal junction,¹ and this is not apparent on our patient’s study.

Review of this patient’s esophagogram also does not reveal any extrinsic compression, esophageal malignancy, or distal tapering suggesting achalasia. In light of the abrupt onset of symptoms related to both solids and liquids associated with atypical chest pain, the primary concern should be for esophageal spasm.

ONE MORE TEST

4. What study would you order next to better elucidate the cause of this patient’s esophageal disorder?

• High-resolution esophageal manometry
• Esophagogastroduodenoscopy (EGD) with endoscopic ultrasonography
• 24-hour pH and impedance testing
• Wireless motility capsule

Esophageal manometry (Figure 2) is used to evaluate the function and coordination of the muscles of the esophagus, as in disorders of esophageal motility.

High-resolution manometry is the gold standard for evaluation of esophageal motility. It is appropriate in evaluating dysphagia or noncardiac chest pain without evidence of mechanical obstruction, ulceration, or inflammation.^4,5

High-resolution manometry differs from conventional manometry in that the catheter has more sensors to measure intraluminal pressure (36 rather than the usual 7 to 12). The data are translated into pressure topography plots (Figure 3).^6,7

Updated guidelines on how to interpret the findings of high-resolution manometry are known as the Chicago 3.0 criteria.⁴ According to this system, esophageal motility disorders are grouped on the basis of lower esophageal sphincter relaxation and then further subdivided based on the character of peristalsis.

EGD with endoscopic ultrasonography would not be appropriate at this time because there is little suspicion of an extraluminal mass that needs to be investigated.

A 24-hour pH and impedance study is helpful in determining the presence of esophageal acid exposure in patients presenting with gastroesophageal reflux disease. This patient does not have symptoms of heartburn or regurgitation; therefore, this investigation would not be of value.

A wireless motility capsule would help in investigating gastric and small-bowel motility and may be useful in the future for this patient, but at this point it would provide little additional utility.

ESOPHAGEAL SPASM

Our patient underwent high-resolution esophageal manometry. The results (Figure 4) revealed a normal resting pressure in the lower esophageal sphincter and complete relaxation in all swallows. The body of the esophagus demonstrated premature contractions in 90% of swallows. Overall, these findings were consistent with the diagnosis of distal esophageal spasm.

In addition to incorporating data obtained from endoscopy, esophagography, and manometry, it is crucial to identify the patient’s predominant symptom when planning treatment. For example, is the prevailing symptom dysphagia or chest pain? Additional consideration must be given to medical, surgical, and psychiatric comorbidities.

5. Which of the following is appropriate medical therapy for esophageal spasm?

• Calcium channel blockers
• Nitrates
• Hydralazine
• Phosphodiesterase 5 (PDE5) inhibitors
• All of the above

All of these have been used to treat distal esophageal spasm as well as other hypercontractile esophageal motility disorders.^8–20

Calcium channel blockers have proven to be effective in randomized controlled trials. Diltiazem has been shown to be beneficial at doses ranging from 60 to 90 mg, as has nifedipine 10 to 20 mg 3 times daily. Although different drugs of this class tend to relax the lower esophageal sphincter to different degrees, when choosing among them in patients with hypercontractile disorders there is little concern for potentially precipitating reflux.^8–13

Nitrates, hydralazine, and PDE5 inhibitors have been effective in uncontrolled studies but have not been studied in randomized trials.^14–17

Other treatments. Patients may also benefit from neuromodulators such as trazodone and imipramine for chest pain and optimization of antisecretory therapy if they have concomitant gastroesophageal reflux disease.^18–20

Patients who have documented esophageal hypercontractility along with reflux disease confirmed by an abnormal pH study show significant improvement in their chest pain symptoms with high doses of a proton pump inhibitor (PPI). As our patient presented with chest pain and dysphagia, a dedicated pH study was not needed, and we could progress straight to manometry and a trial of a PPI.

Our patient was started on a PPI and nifedipine but developed a pruritic rash. As rash does not preclude using another medication in the same class, his treatment was changed to diltiazem 30 mg by mouth 3 times a day, and his dysphagia improved. However, he continued to experience intermittent chest pain with swallowing. After discussion of neuromodulator therapy, he declined additional pharmacologic therapy.

A NONPHARMACOLOGIC TREATMENT?

6. Which of the following would you offer this patient as a nonpharmacologic alternative for his esophageal pain?

• St. John’s wort
• Ginkgo biloba
• Ginseng
• Peppermint extract
• Eucalyptus oil

In a small, open-label study in patients with esophageal spasm, the use of 5 drops of commercially available 11% peppermint extract in 10 mL of water significantly decreased simultaneous contractions and resolved chest pain.²¹ Esophageal manometry was performed 10 minutes after the peppermint solution was consumed, and the results showed improvement in esophageal spasm. While the authors of this study did not make any formal recommendations, the findings suggest that peppermint extract should be given 10 minutes before meals.

There is no evidence for or against the use of the other nonpharmacologic treatments mentioned here.

PAIN RELIEF

7. If a pharmacologic approach were chosen, which would be the best option for pain relief in this patient?

• Oxycodone 5 mg every 8 hours
• Acetaminophen 650 mg every 8 hours
• Ibuprofen 400 mg every evening at bedtime
• Trazodone 100 mg every evening at bedtime
• Imipramine 50 mg every evening at bedtime
• Aripiprazole 5 mg by mouth every day

Trazodone would be the most appropriate of these options. Doses of 100 mg to 150 mg every evening at bedtime have been shown to significantly improve global assessment scores of pain at 6 weeks.¹⁸

Imipramine 50 mg every evening at bedtime would be another option and also has been shown to reduce chest pain.¹⁹

Even though these were the doses that were investigated, in clinical practice it is common to start at lower doses (trazodone 50 mg or imipramine 10 mg) and to then titrate every 4 weeks based on the patient’s response.

Opiates (eg, oxycodone) should be avoided, as they can cause esophageal motility disorders such as spasm or achalasia.²²

Acetaminophen and aripiprazole have not been studied exclusively for their effect on chest pain related to esophageal spasm.

RECURRENT SYMPTOMS

The patient’s dysphagia initially decreased while he was taking diltiazem 30 mg 3 times a day, but it recurred after 6 months. The dosage was increased to 60 mg 3 times a day over the course of the next year, with minimal response. (The maximum dose is 90 mg 4 times a day, but because of side effects of lightheadedness and dizziness, out patient could not tolerate more than 60 mg 3 times a day).

8. What endoscopic therapies are appropriate for patients with esophageal spasm that does not respond to medication?

• Bougie dilation
• Balloon dilation
• Onabotulinum toxin injection
• Expandable mesh stent placement
• Mucosal sclerotherapy

Onabotulinum toxin injections have been shown to improve dysphagia when given in a linear pattern.²³

Endoscopic dilation has not been shown to be beneficial in this setting, as a study found no difference in efficacy between therapeutic (54-French) and sham (24-French) bougie dilation.²⁴

Our patient received 100 units of onabotulinum toxin (10 units every centimeter in the distal 10 cm of the esophagus). Afterward, he experienced resolution of dysphagia, with only mild intermittent chest pain, which was controlled by taking peppermint extract as needed. The symptoms returned approximately 1 year later but responded to repeat endoscopy with onabotulinum toxin injections.^23,25

Peroral endoscopic myotomy

Another relatively new endoscopic treatment for esophageal motility disorders is peroral endoscopic myotomy (Figure 5). During this procedure a tiny incision is made in the esophageal mucosa, permitting the endoscope to tunnel within the lining. The smooth muscle of the distal esophagus and lower esophageal sphincter is then cut, thereby freeing either the spastic muscle (in distal esophageal spasm) or the hyperactive lower esophageal sphincter (in achalasia).^26,27

In an open trial, after undergoing peroral endoscopic myotomy for esophageal spasm and hypercontractile esophagus, 89% of patients had complete relief of dysphagia, and 92% had palliation of chest pain.²⁸ Of note, the rate of relief of dysphagia was higher for patients with achalasia (98%) than for nonachalasia patients (71%).

A 71-year-old man was referred to the gastroenterology department for evaluation of 9 months of progressive swallowing difficulties associated with epigastric and chest discomfort.

He was a previous smoker (17 pack-years), with a history of coronary artery disease, hypertension, and cervical spinal stenosis requiring decompressive laminectomy with a postoperative course complicated by episodes of aspiration.

DYSPHAGIA: OROPHARYNGEAL OR ESOPHAGEAL

Difficulty swallowing (dysphagia) can be caused by problems in the oropharynx or in the esophagus. Difficulty initiating a swallow can be thought of as oropharyngeal dysphagia, whereas the intermittent sensation of food stuck in the neck or chest is considered esophageal dysphagia.

Focused questioning can help differentiate oropharyngeal symptoms from esophageal symptoms. For example, difficulty clearing secretions or passing the food bolus beyond the mouth or frequent coughing spells while eating is consistent with oropharyngeal dysphagia and suggests a neurologic cause. Our patient, however, presented with a constellation of symptoms more suggestive of esophageal dysphagia.

When eliciting a history of esophageal symptoms, it is crucial to determine the progression of swallowing difficulty, as well as how it directly relates to eating solids or liquids, or both. Difficulty swallowing solid foods that has progressed over time to include liquids would raise concern for an obstruction such as a stricture, ring, or malignancy. On the other hand, abrupt onset of intermittent dysphagia to both solids and liquids would raise concern for a motility disorder of the esophagus. This patient presented with an abrupt onset of intermittent symptoms to both solids and liquids that was associated with substernal chest pain.

Once coronary disease was ruled out by cardiac biomarker testing, electrocardiography, and a pharmacologic stress test, our patient underwent upper endoscopy, which showed a normal esophageal mucosa without masses or obstruction and no evidence of peptic ulcer disease.

WHAT IS THE NEXT STEP?

When upper endoscopy is negative and cardiac causes and gastroesophageal reflux disease have been ruled out, an esophageal motility disorder should be considered.

1. After obstruction has been ruled out with upper endoscopy, which should be the next step in the investigation of esophageal dysphagia?

• A 24-hour pH recording
• Barium esophagography
• Modified barium swallow
• Computed tomography of the chest

Barium esophagography is the optimal fluoroscopic study to evaluate the esophageal phase of the swallow. This study requires the patient to swallow a thick barium solution and a 13-mm barium pill under video analysis. It is useful early in the investigation of esophageal dysphagia because it can potentially reveal areas of esophageal luminal narrowing not detected endoscopically, as well as detail the rate of esophageal emptying.¹

The modified barium swallow, which is performed with the assistance of a speech pathologist, is similar but only shows the oropharynx as far as the cervical esophagus. Therefore, it would be the best fluoroscopic test to assess patients with possible aspiration or oropharyngeal dysphagia, whereas barium esophagography would be the test of choice in evaluating esophageal dysmotility or mechanical obstruction.

pH testing may be helpful in diagnosing gastroesophageal reflux disease but is less helpful in the evaluation of dysphagia.

Computed tomography of the chest may be useful to evaluate for extrinsic compression of the esophagus, but it is not the best next step in the evaluation of dysphagia.

Our patient underwent barium esophagography, which revealed tertiary contractions in the mid and distal esophagus with slight narrowing of the lower cervical esophagus (Figure 1). (Primary contractions are elicited when initiating a swallow that propels the food bolus through the esophagus, while secondary contractions follow in response to esophageal distention to move all remaining esophageal contents from the thoracic esophagus. Tertiary contractions are abnormal, nonpropulsive, spontaneous contractions of the esophageal body that are initiated without swallowing.²)

EOSINOPHILIC ESOPHAGITIS

Histologic study of biopsies of the mid and distal esophagus from our patient’s upper endoscopy revealed 5 eosinophils per high-power field.

2. Does this patient meet the criteria for the diagnosis of eosinophilic esophagitis?

• Yes
• No

No. Having eosinophils in the esophagus is not enough to diagnose eosinophilic esophagitis, as eosinophils are also common in patients with gastroesophageal reflux disease.

Eosinophilic esophagitis is defined as a chronic immune-mediated esophageal disease with histologically eosinophil-predominant inflammation (with more than 15 eosinophils per high-power field). The diagnosis is additionally based on symptoms and endoscopic appearance.³ When investigating possible eosinophilic esophagitis, it is recommended that 2 to 4 samples be obtained from at least 2 different locations in the esophagus (eg, proximal and distal), because the inflammatory changes can be patchy.

3. What is the likely cause of this patient’s dysphagia?

• Eosinophilic esophagitis
• Achalasia
• Esophageal spasm
• Extrinsic compression
• Esophageal malignancy

Eosinophilic esophagitis causes characteristic symptoms that include difficulty swallowing, chest pain that does not respond to antisecretory therapy, and regurgitation of undigested food. As we discussed above, this patient has only 5 eosinophils per high-power field and does not meet the histologic criteria for eosinophilic esophagitis.

Achalasia has a characteristic “bird’s beak” appearance on esophagography that results from distal tapering of the esophagus to the gastroesophageal junction,¹ and this is not apparent on our patient’s study.

Review of this patient’s esophagogram also does not reveal any extrinsic compression, esophageal malignancy, or distal tapering suggesting achalasia. In light of the abrupt onset of symptoms related to both solids and liquids associated with atypical chest pain, the primary concern should be for esophageal spasm.

ONE MORE TEST

4. What study would you order next to better elucidate the cause of this patient’s esophageal disorder?

• High-resolution esophageal manometry
• Esophagogastroduodenoscopy (EGD) with endoscopic ultrasonography
• 24-hour pH and impedance testing
• Wireless motility capsule

Esophageal manometry (Figure 2) is used to evaluate the function and coordination of the muscles of the esophagus, as in disorders of esophageal motility.

High-resolution manometry is the gold standard for evaluation of esophageal motility. It is appropriate in evaluating dysphagia or noncardiac chest pain without evidence of mechanical obstruction, ulceration, or inflammation.^4,5

High-resolution manometry differs from conventional manometry in that the catheter has more sensors to measure intraluminal pressure (36 rather than the usual 7 to 12). The data are translated into pressure topography plots (Figure 3).^6,7

Updated guidelines on how to interpret the findings of high-resolution manometry are known as the Chicago 3.0 criteria.⁴ According to this system, esophageal motility disorders are grouped on the basis of lower esophageal sphincter relaxation and then further subdivided based on the character of peristalsis.

EGD with endoscopic ultrasonography would not be appropriate at this time because there is little suspicion of an extraluminal mass that needs to be investigated.

A 24-hour pH and impedance study is helpful in determining the presence of esophageal acid exposure in patients presenting with gastroesophageal reflux disease. This patient does not have symptoms of heartburn or regurgitation; therefore, this investigation would not be of value.

A wireless motility capsule would help in investigating gastric and small-bowel motility and may be useful in the future for this patient, but at this point it would provide little additional utility.

ESOPHAGEAL SPASM

Our patient underwent high-resolution esophageal manometry. The results (Figure 4) revealed a normal resting pressure in the lower esophageal sphincter and complete relaxation in all swallows. The body of the esophagus demonstrated premature contractions in 90% of swallows. Overall, these findings were consistent with the diagnosis of distal esophageal spasm.

In addition to incorporating data obtained from endoscopy, esophagography, and manometry, it is crucial to identify the patient’s predominant symptom when planning treatment. For example, is the prevailing symptom dysphagia or chest pain? Additional consideration must be given to medical, surgical, and psychiatric comorbidities.

5. Which of the following is appropriate medical therapy for esophageal spasm?

• Calcium channel blockers
• Nitrates
• Hydralazine
• Phosphodiesterase 5 (PDE5) inhibitors
• All of the above

All of these have been used to treat distal esophageal spasm as well as other hypercontractile esophageal motility disorders.^8–20

Calcium channel blockers have proven to be effective in randomized controlled trials. Diltiazem has been shown to be beneficial at doses ranging from 60 to 90 mg, as has nifedipine 10 to 20 mg 3 times daily. Although different drugs of this class tend to relax the lower esophageal sphincter to different degrees, when choosing among them in patients with hypercontractile disorders there is little concern for potentially precipitating reflux.^8–13

Nitrates, hydralazine, and PDE5 inhibitors have been effective in uncontrolled studies but have not been studied in randomized trials.^14–17

Other treatments. Patients may also benefit from neuromodulators such as trazodone and imipramine for chest pain and optimization of antisecretory therapy if they have concomitant gastroesophageal reflux disease.^18–20

Patients who have documented esophageal hypercontractility along with reflux disease confirmed by an abnormal pH study show significant improvement in their chest pain symptoms with high doses of a proton pump inhibitor (PPI). As our patient presented with chest pain and dysphagia, a dedicated pH study was not needed, and we could progress straight to manometry and a trial of a PPI.

Our patient was started on a PPI and nifedipine but developed a pruritic rash. As rash does not preclude using another medication in the same class, his treatment was changed to diltiazem 30 mg by mouth 3 times a day, and his dysphagia improved. However, he continued to experience intermittent chest pain with swallowing. After discussion of neuromodulator therapy, he declined additional pharmacologic therapy.

A NONPHARMACOLOGIC TREATMENT?

6. Which of the following would you offer this patient as a nonpharmacologic alternative for his esophageal pain?

• St. John’s wort
• Ginkgo biloba
• Ginseng
• Peppermint extract
• Eucalyptus oil

In a small, open-label study in patients with esophageal spasm, the use of 5 drops of commercially available 11% peppermint extract in 10 mL of water significantly decreased simultaneous contractions and resolved chest pain.²¹ Esophageal manometry was performed 10 minutes after the peppermint solution was consumed, and the results showed improvement in esophageal spasm. While the authors of this study did not make any formal recommendations, the findings suggest that peppermint extract should be given 10 minutes before meals.

There is no evidence for or against the use of the other nonpharmacologic treatments mentioned here.

PAIN RELIEF

7. If a pharmacologic approach were chosen, which would be the best option for pain relief in this patient?

• Oxycodone 5 mg every 8 hours
• Acetaminophen 650 mg every 8 hours
• Ibuprofen 400 mg every evening at bedtime
• Trazodone 100 mg every evening at bedtime
• Imipramine 50 mg every evening at bedtime
• Aripiprazole 5 mg by mouth every day

Trazodone would be the most appropriate of these options. Doses of 100 mg to 150 mg every evening at bedtime have been shown to significantly improve global assessment scores of pain at 6 weeks.¹⁸

Imipramine 50 mg every evening at bedtime would be another option and also has been shown to reduce chest pain.¹⁹

Even though these were the doses that were investigated, in clinical practice it is common to start at lower doses (trazodone 50 mg or imipramine 10 mg) and to then titrate every 4 weeks based on the patient’s response.

Opiates (eg, oxycodone) should be avoided, as they can cause esophageal motility disorders such as spasm or achalasia.²²

Acetaminophen and aripiprazole have not been studied exclusively for their effect on chest pain related to esophageal spasm.

RECURRENT SYMPTOMS

The patient’s dysphagia initially decreased while he was taking diltiazem 30 mg 3 times a day, but it recurred after 6 months. The dosage was increased to 60 mg 3 times a day over the course of the next year, with minimal response. (The maximum dose is 90 mg 4 times a day, but because of side effects of lightheadedness and dizziness, out patient could not tolerate more than 60 mg 3 times a day).

8. What endoscopic therapies are appropriate for patients with esophageal spasm that does not respond to medication?

• Bougie dilation
• Balloon dilation
• Onabotulinum toxin injection
• Expandable mesh stent placement
• Mucosal sclerotherapy

Onabotulinum toxin injections have been shown to improve dysphagia when given in a linear pattern.²³

Endoscopic dilation has not been shown to be beneficial in this setting, as a study found no difference in efficacy between therapeutic (54-French) and sham (24-French) bougie dilation.²⁴

Our patient received 100 units of onabotulinum toxin (10 units every centimeter in the distal 10 cm of the esophagus). Afterward, he experienced resolution of dysphagia, with only mild intermittent chest pain, which was controlled by taking peppermint extract as needed. The symptoms returned approximately 1 year later but responded to repeat endoscopy with onabotulinum toxin injections.^23,25

Peroral endoscopic myotomy

Another relatively new endoscopic treatment for esophageal motility disorders is peroral endoscopic myotomy (Figure 5). During this procedure a tiny incision is made in the esophageal mucosa, permitting the endoscope to tunnel within the lining. The smooth muscle of the distal esophagus and lower esophageal sphincter is then cut, thereby freeing either the spastic muscle (in distal esophageal spasm) or the hyperactive lower esophageal sphincter (in achalasia).^26,27

In an open trial, after undergoing peroral endoscopic myotomy for esophageal spasm and hypercontractile esophagus, 89% of patients had complete relief of dysphagia, and 92% had palliation of chest pain.²⁸ Of note, the rate of relief of dysphagia was higher for patients with achalasia (98%) than for nonachalasia patients (71%).

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.

Gastroesophageal reflux disease (GERD) is a chronic and common medical problem, with up to 40% of the population experiencing its symptoms at least once per month.¹ The condition develops when the reflux of stomach contents causes troublesome symptoms or complications.²

GERD symptoms can range from heartburn and regurgitation to cough and hoarseness. While many patients’ symptoms respond to medical treatment, the diagnosis and treatment in those whose symptoms do not respond to a proton pump inhibitor (PPI) may be challenging.

This article reviews the diagnosis and treatment options for GERD.

SYMPTOMS: TYPICAL, ATYPICAL, AND ALARM

Symptoms of GERD (Table 1) can be classified as typical (heartburn and regurgitation) or atypical (cough, asthma, hoarseness, chronic laryngitis, throat-clearing, chest pain, dyspepsia, and nausea). Atypical symptoms are more likely to be due to GERD if patients also have typical symptoms and if the symptoms respond to a trial of a PPI.³

Alarm symptoms. Keep in mind that extraesophageal presentations may be multifactorial, and it may be difficult to establish that reflux, even if present, is actually the cause. While chest pain may be due to GERD, it is important to rule out cardiac chest pain before considering GERD as a cause. Similarly, dysphagia along with typical or atypical symptoms warrants investigation for potential complications such as underlying motility disorder, esophageal stricture, esophageal ring, or malignancy.⁴ Other alarm symptoms include odynophagia, bleeding, weight loss, and anemia.

DIAGNOSING GERD: RESPONSE TO A PPI IS DIAGNOSTIC

Patients with typical symptoms that respond to PPI therapy need no further evaluation for a diagnosis of GERD to be made.⁵ On the other hand, further testing should be undertaken in patients with typical symptoms that do not respond to PPI therapy, in patients presenting with atypical symptoms, and in patients in whom antireflux surgery is being considered. Figure 1 shows our proposed algorithm.

Try a PPI for 6–8 weeks

Relief of heartburn and regurgitation after a 6- to 8-week course of a PPI strongly suggests GERD.⁶ However, a negative trial of a PPI does not rule out GERD, as this approach has been found to have a sensitivity of 78% and specificity of 54%.⁶

Despite this limitation, a trial of PPI therapy should be offered to patients presenting with typical symptoms and no alarm features. This approach has been found to be more cost-effective than proceeding directly to diagnostic testing.⁷

Endoscopy

Endoscopic findings in GERD can include erosive esophagitis, peptic stricture, and Barrett esophagus. Esophageal erosions are a highly specific sign of GERD; the Los Angeles classification system, a standardized scale for grading the severity of erosive esophagitis (from A to D, with D the most severe) provides an objective way to assess severity.⁸ However, most patients with heartburn and regurgitation do not have erosive disease, thus limiting the sensitivity of upper endoscopy as an initial diagnostic test in patients with suspected GERD.⁹

We recommend endoscopy for patients who present with alarm symptoms, patients with noncardiac chest pain, PPI nonresponders, and patients with chronic GERD symptoms and multiple risk factors for Barrett esophagus besides GERD, such as older age, male sex, white race, overweight, and smoking.¹⁰

Ambulatory pH and impedance monitoring

Ambulatory pH monitoring is the gold standard test for pathologic acid exposure in the esophagus. pH testing is indicated in PPI nonresponders, patients presenting with atypical symptoms, and before antireflux surgery.

In general, pH testing should be performed after the patient has been off PPI therapy for at least 7 days, as the test is highly unlikely to be abnormal while a patient is on a PPI.¹¹ It is done either with a transnasal catheter for 24 hours, or with a wireless capsule (Bravo pH System, Given Imaging Ltd, Duluth, GA), which collects 48 to 96 hours of data. Studies of the wireless system have shown that its sensitivity increases 12% to 25% when it is performed for 48 hours compared with 24 hours.^12,13

The pH test can be combined with impedance testing to evaluate for nonacid reflux.¹⁴ However, the clinical significance of nonacid reflux remains controversial, and for this reason the Esophageal Diagnostic Advisory Panel recommends that the decision to perform antireflux surgery should not be based on abnormal impedance testing.¹⁵

Ambulatory pH monitoring is the gold-standard test

During pH and impedance testing, special software can calculate how closely the patient’s symptoms correlate with esophageal acid exposure. The symptom index (SI) and symptom association probability (SAP) are the symptom measurements most commonly used in practice. The SI measures the overall strength of the relationship, and an SI greater than 50% is considered positive.¹⁶ The SAP determines whether this relationship could have occurred by chance, and an SAP greater than 95% is statistically significant.¹⁷ In patients with normal levels of esophageal acid exposure, an elevated SI or SAP may indicate a component of esophageal hypersensitivity in symptom generation.

At our institution, we generally perform pH-only transnasal or wireless testing off PPI therapy to establish that the patient has pathologic acid exposure in the distal esophagus. Combined pH-impedance testing is typically reserved for patients with atypical symptoms unresponsive to PPI therapy and abnormal results on previous pH testing, which allows for correlation of nonacid reflux and symptoms.

Other tests

Esophageal manometry and barium esophagography have limited value in the primary diagnosis of GERD. However, they should be considered to rule out achalasia and other esophageal motility disorders in patients whose symptoms do not respond to PPIs. For this reason, esophageal manometry should be performed before considering antireflux surgery.

MANAGING GERD

Table 2 summarizes the various treatments for GERD.

Lifestyle modifications

Lifestyle modifications are the first-line therapy for GERD. Modifications that have been studied include weight loss, head-of-bed elevation, and avoidance of tobacco, alcohol, and late-night meals. Another modification that has been suggested is avoiding foods that can aggravate reflux symptoms—eg, caffeine, coffee, chocolate, spicy foods, highly acidic foods (oranges, tomatoes), and fatty foods. Of these, only weight loss and head-of-bed elevation have been proven effective.¹⁸

Three randomized controlled trials demonstrated that GERD symptoms and esophageal pH values improved with head-of-bed elevation using blocks or incline foam wedges.^19–21 Several cohort studies demonstrated reduction in GERD symptoms with weight loss.^22,23 Recently, a prospective cohort study also found that smoking cessation significantly improved GERD symptoms in patients with normal body mass index and severe symptoms.²⁴

Antacids

Several antacids (eg, sodium bicarbonate, calcium carbonate, magnesium hydroxide, aluminum hydroxide) are available over the counter.

Antacids were thought to control heartburn symptoms by increasing the pH of gastric contents that might subsequently reflux into the esophagus. However, well-controlled studies have shown that they relieve heartburn by neutralizing acid in the esophagus, with no significant effect on gastric pH.^25,26

Antacids provide rapid but short-lived relief from an existing episode of heartburn. Because they do not significantly raise the gastric pH, they do not prevent subsequent reflux episodes from repeatedly exposing the esophagus to gastric acid and causing heartburn. Additionally, antacids have not been shown to contribute to healing of erosive esophagitis.²⁷ Hence, they may not be optimal for treating frequent reflux heartburn.

Sodium alginate

Gastric acid pockets are unbuffered pools of acid that float on top of ingested food.²⁸ They develop as a result of poor mixing of newly secreted acid and food in the proximal stomach, which remains relatively quiescent after a meal compared with the distal stomach.²⁹ In GERD, proximal extension of the acid pocket above the diaphragm increases the risk of acid reflux.³⁰ The acid pocket is therefore an important source of postprandial acid in GERD and, as such, represents a unique therapeutic target.

Emerging evidence suggests that alginates may act directly on the acid pocket. Alginates are natural polysaccharide polymers that, on contact with gastric acid, precipitate within minutes into a low-density viscous gel of near-neutral pH. The change in pH triggers the sodium bicarbonate in the formulation to release carbon dioxide that becomes trapped in the alginate gel, causing it to float to the top of the gastric contents like a raft.³¹

A randomized controlled trial demonstrated that sodium alginate was as effective as omeprazole in relieving symptoms in patients with nonerosive reflux disease.³² Alginate has also been shown to provide more postprandial reflux relief than antacids.³³

Histamine-2 receptor antagonists

Histamine-2 receptor antagonists act more swiftly and increase postprandial gastric pH more rapidly than PPIs, thus making them a good option for prophylaxis against postprandial GERD.³⁴ Taking these drugs at bedtime may help in patients with objective nighttime reflux despite optimal PPI use. However, tachyphylaxis may occur as early as 1 week after starting combination therapy.³⁵

Proton pump inhibitors

There are currently seven available PPIs, including four that can be obtained over the counter (omeprazole, lansoprazole, esomeprazole, and omeprazole-sodium bicarbonate) and three available only by prescription (rabeprazole, pantoprazole, and dexlansoprazole). Studies have shown than a standard 6- to 8-week course of a PPI provides complete symptom relief in 70% to 80% of patients with erosive reflux disease and in 60% of patients with nonerosive reflux disease.^36,37 Clinically, PPIs all appear to be similar in their symptom relief.³⁸

Most PPIs should be taken 30 to 60 minutes before meals. Exceptions are omeprazole-sodium bicarbonate and dexlansoprazole, which can be taken without regard to meals. At our institution, we usually start PPIs in a once-daily standard dose for 6 to 8 weeks and consider increasing to twice-daily dosing if symptoms do not respond completely. Patients with mild intermittent GERD symptoms may benefit from “on-demand” use of PPIs. This approach is best suited for patients with nonerosive reflux disease without evidence of Barrett esophagus on endoscopy.

Safety and adverse effects of PPIs

PPIs are generally safe but can cause adverse effects (Table 3).

Osteoporosis. In 2010, the US Food and Drug Administration issued warnings regarding the potential for wrist, hip, and spine fractures in PPI users.²⁶ Most recent evidence suggests that PPIs may be associated with a small increase in risk of hip fractures in patients already at high risk.^39,40 However, the 2013 American College of Gastroenterology (ACG) guidelines say that patients with known osteoporosis can remain on PPI therapy, and concern for hip fractures and osteoporosis should not affect the decision to use PPIs long-term except in patients with other risk factors for hip fracture.⁴¹

Community-acquired pneumonia. An increased risk of community-acquired pneumonia cannot be clearly documented in association with PPI therapy. Multiple studies, including randomized controlled trials, investigated this potential correlation. However, evidence suggests that short-term but not long-term PPI use may be associated with an overall increased risk of community-acquired pneumonia.^42,43 Current guidelines suggest that in patients who need a PPI, the drug should not be withheld on the basis of a potential risk of community-acquired pneumonia.⁴¹

Clostridium difficile infection. In theory, PPIs may increase the risk of C difficile infection by increasing the ability of the spore to convert to the vegetative form and to survive intraluminally. In fact, studies and meta-analyses have suggested that PPIs do increase the risk of development and recurrence of C difficile infection.^44,45 Therefore, PPIs should be used with care in patients who are at risk.⁴¹

Interaction with clopidogrel. The antiplatelet activity of clopidogrel requires activation by CYP2C19, the same pathway required for metabolism of some PPIs. Concern was raised about decreased antiplatelet activity of clopidogrel in the presence of PPIs. This was extensively studied, and there now appears to be no increased risk of adverse cardiovascular events in patients on PPIs, based on data from well-controlled randomized trials.^46,47 A consensus panel of the American College of Cardiology Foundation, the American Heart Association, and the ACG said that PPIs may be used for appropriate indications in patients taking clopidogrel.⁴⁷

Hypomagnesemia. By an unknown molecular mechanism, PPIs are thought to reduce intestinal magnesium absorption, leading to hypomagnesemia. A meta-analysis published in 2011 showed that PPI-induced hypomagnesemia is a drug-class effect and occurred after a median of 5.5 years of PPI use. Stopping the PPI resulted in magnesium recovery in 4 days, and rechallenge led to recurrence within 4 days.⁴⁸

Hence, to avoid putting patients on long-term PPI therapy at risk, clinicians should anticipate this problem. Our practice is to check the magnesium level before starting a patient on long-term PPI therapy, and then to repeat the measurement every 1 to 2 years.

Baclofen

Transient lower esophageal sphincter relaxation has been shown to be a cause of reflux in healthy people and in patients with GERD.⁴⁹

Baclofen, a muscle relaxant with selective gamma-aminobutyric acid receptor class B agonist properties, reduces transient lower esophageal sphincter relaxation in humans.⁵⁰ In a well-designed, double-blind, randomized controlled trial, baclofen was associated with a significant decrease in upright reflux on 24-hour pH monitoring and significant improvement in belching and overall reflux symptoms.⁵¹ However, baclofen is not approved by the US Food and Drug Administration for the treatment of GERD, and its use may be limited by side effects such as somnolence and dizziness.

Antireflux surgery

Antireflux surgery is a reasonable option for selected patients with chronic GERD. The main types of surgery are laparoscopic fundoplication and, for obese patients, gastric bypass. Reasons to consider antireflux surgery include desire to stop PPI therapy, esophagitis not healed by PPIs, symptomatic hiatal hernia, and refractory reflux documented by pH testing.⁴¹

Clinically, all PPIs appear to be similar in their symptom relief

In general, surgical therapy may be considered in patients who respond to PPIs, but patients who do not respond to PPIs are less likely to respond to antireflux surgery.¹⁵ Other patients less likely to respond are those with symptoms of dyspepsia, such as nausea, vomiting, and epigastric pain.⁴¹

Common adverse effects of antireflux surgery include gas-bloat syndrome (up to 85% of patients), dysphagia (10% to 50% of patients), diarrhea (18% to 33% of patients), and recurrent heartburn (10% to 62% of patients).⁵²

Endoscopic and minimally invasive antireflux procedures include endoscopic plication of the lower esophageal sphincter, radiofrequency augmentation of the lower esophageal sphincter, and sphincter augmentation by a string of titanium beads. While some have shown promise, they are not recommended by the most recent ACG guidelines, given lack of long-term data.⁴¹

REFRACTORY GERD

There is no consensus on the definition of refractory GERD. However, for the sake of simplicity, we can define it as persistence of suspected GERD symptoms despite treatment with a PPI. This may vary from a partial response to PPI therapy to a complete absence of response.

It is extremely important to rule out non-GERD causes of the ongoing symptoms, such as achalasia, gastroparesis, eosinophilic esophagitis, rumination, and aerophagia. PPI nonresponders are more likely to be obese, poorly compliant, and have extraesophageal symptoms.^53–56 As previously discussed, PPIs should be taken 30 to 60 minutes before meals. For patients whose symptoms fail to respond to standard-dose daily PPI therapy, switching to another PPI or doubling the dose is common, although data to support this practice are limited. Of note, omeprazole-sodium bicarbonate has been shown to provide more symptom relief in nocturnal GERD.⁵⁷ Additionally, adding a nighttime histamine-2 receptor antagonist may also help in patients with objective nighttime reflux.⁴¹

After noncompliance and suboptimal PPI dosing have been ruled out, PPI nonresponders with typical symptoms should undergo upper endoscopy and subsequent pH monitoring. Normal esophageal acid exposure on pH testing suggests functional heartburn or functional dyspepsia. Negative pH testing in a patient with atypical symptoms suggests a non-GERD cause of symptoms, and referral to an otolaryngologist, pulmonologist, or allergist is often warranted.

While antireflux surgery can be considered for patients with nonacid reflux on impedance testing, it should again be noted that GERD in patients with no response to PPIs is less likely to respond to antireflux surgery.¹⁵

TAKE-HOME POINTS

• GERD is a common medical condition, affecting up to 40% of US adults at least once monthly.
• GERD can result in a wide variety of symptoms, including typical heartburn and regurgitation as well as atypical symptoms such as cough.
• On the other hand, keep in mind that multiple non-GERD causes of heartburn and regurgitation may exist.
• Testing for GERD includes endoscopy and pH testing as well as functional testing such as esophageal manometry.
• While in most patients GERD will respond to lifestyle changes and antisecretory therapy such as a PPI, careful attention must be given to patients with symptoms refractory to PPI therapy.
• For a subset of patients, antireflux surgery may be a reasonable option, but care must be taken to exclude patients with a lower likelihood of responding to surgery.