The wireless system (Bravo capsule) of esophageal pH measurement, compared with pH equipment with probes, is better tolerated by the patient and has greater sensitivity for detecting acid reflux and establishing the association of symptoms with reflux episodes. Its limitations are cost and availability, chest pain, and the fact that it does not detect non-acid reflux.26–28

Antacids and alginates are recommended for symptom relief and do not contribute to erosion cicatrization or prevent the development of complications.51,52 There is no evidence supporting their chronic use.

H2RAs should not be used as first-line treatment and are auxiliaries in PPI management.53 They can be used in cases of GERD with typical and sporadic symptoms. They can also be used as treatment in cases of NERD if they produce symptom relief and in cases of nocturnal GERD (together with a PPI in the morning), but they are recommended for short periods since tachyphylaxis is produced in 7 days.54,55 They are also indicated in GERD in the context of PPI hypersensitivity or side effects.

There is no evidence for its recommendation.12

These medications should not be used as the sole treatment in GERD management. When symptoms suggest gastric emptying alterations (e.g. overlap with dyspepsia), prokinetics can be used in combination with a PPI.2,56,57

It is important to be aware that prokinetics can have relevant side effects that should be watched for, such as hyperprolactinemia, late dyskinesia, diarrhea, and headache.

PPIs are first-choice medications for the treatment of GERD in all its clinical forms, given that they provide greater and faster symptom relief, as well as higher cicatrization percentages, compared with placebo, antacids, and H2RAs.51–55,58

There are currently various PPIs (Table 3) and all of them, when adequately prescribed, are efficacious.2,12,53 Even though studies show varying rates in intragastric pH control and symptom response, meta-analyses have shown that effectiveness among the different PPIs is similar.59

It is important to instruct patients that “conventional” PPIs should be taken at least 30min before breakfast, because that is the time of day in which there is a greater quantity of active pumps in the parietal cells.12 A dual delayed-release PPI, dexlansoprazole, has recently become available. In pharmacokinetic studies, it has been shown to maintain adequate therapeutic levels, regardless of food intake, which facilitates treatment adherence.60 Some studies have even recommended dexlansoprazole use as management therapy in patients with NERD that have achieved symptom control with double doses of conventional PPIs.61 However, more studies are needed comparing dexlansoprazole with the other PPIs. A combination of omeprazole and bicarbonate with no enteric coating layer is also available in Mexico and is considered a drug of immediate release, which apparently has a faster effect. Nevertheless, more studies with respect to this are required.

In general, PPIs are considered safe and adverse effects are rare (< 2%), the most common of which are: nausea, diarrhea, headache, insomnia, and anaphylaxis.62

In regard to long-term safety, some adverse effects have been described in the last few years: osteoporosis,63,64 vitamin deficiencies,65 hyperplastic polyps,66 interaction with medications (clopidogrel),67,68 bacterial overgrowth, and Clostridium difficile infection.69–71

Due to this, numerous meta-analyses have been conducted with controversial results. Nevertheless, evidence allows the following recommendations to be made:

• •

  Chronic PPI use, especially in subjects over 65 years of age, is a risk factor for C. difficile and other enteric infections, such as Salmonella and Campylobacter.69

• •

  Chronic PPI use should not be considered the sole risk factor for osteoporosis.64

• •

  Even though short-term PPI use is associated with the development of community-acquired pneumonia in a high-risk population, it is no greater than that associated with H2RA use.70,71

• •

  Concomitant PPI use with clopidogrel does not increase the risk for cardiovascular events.67,68

At present, baclofen has shown greater usefulness for reducing TLESRs. This drug is not available in Mexico, but there is moderate evidence that the use of this GABA-β agonist reduces transient sphincter relaxations, thus reducing reflux episodes (acid and non-acid).72,73 It is recommended as an adjuvant to PPIs in patients with failed response to these, although its high incidence of adverse effects must be taken into account, such as headache, dizziness, and constipation, limiting its clinical use.

The standard PPI dose is recommended in these cases (Table 3) for a period of 4 weeks (fig. 3).2,12,58 If symptom control is achieved, the medication should be suspended and reinitiated in case of relapse.74,75

Figure 3.

Nonerosive reflux disease management. In the proposed maintenance regimens, the red ovals indicate symptom reappearance. For example, in the on-demand regimen, once symptoms appear, treatment is given for the length of time the patient has symptoms (white rectangles); in the intermittent regimen, treatment duration can vary from 2 to 4 weeks, even when symptoms are no longer present.

PPI: proton pump inhibitor.

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If there is recurrence, the following maintenance regimens with PPIs can be employed:

• a.

  Continuous: uninterruptedly use the minimum PPI dose that provides symptom control.73

• b.

  On-demand: use the standard dose every time the patient presents with symptoms and suspend it when they have been controlled.72

• c.

  Intermittent: use the standard dose for defined periods of at least 2-4 weeks every time there is symptom recurrence.73

Another maintenance option is to switch from a PPI to a H2RA, using the latter for short periods and only in the case of mild or intermittent symptoms.76

If response is partial or nonexistent with the initial PPI dose, the following situations should be investigated (fig. 3):77

• •

  adequate drug prescription and administration

• •

  product quality

• •

  treatment adherence

If none of the abovementioned applies, then doubling the dose (see Table 3), changing the PPI, or dividing the dose during the day (if there are nocturnal symptoms) are strategies that should be tried.78–82 If there is no symptom control despite taking these measures, the patient should be re-evaluated (see Diagnosis) and categorized as having PPI failure or refractory GERD.

In cases of ERD, 8-week PPI treatment achieves symptom control and endoscopic cure of lesions in more than 80% of the cases.2,12,51 Duration depends on lesion severity (Fig. 4).

Figure 4.

Erosive reflux disease management.

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In cases of esophagitis C and D, experts recommend repeat endoscopy study at 8 to 12 weeks from the beginning of treatment to rule out BE that has been hidden by inflammation. Due to the fact that in C and D cases recurrence is nearly 100% at 6 months, endoscopic evaluation is recommended upon treatment completion.77,83 Maintenance treatment should be individualized in those cases and evaluated in accordance with patient expectations and his or her environment. These are options that can include continuous PPI treatment and even the possibility of surgical treatment (see Surgical treatment section).

Extraesophageal manifestations with typical symptoms: in patients with extra-esophageal symptoms (laryngitis, cough, and asthma) that also suffer from typical symptoms (heartburn and/or regurgitation), beginning therapy with a PPI trial (double dose for 8 to 12 weeks) is indicated.12 In these cases the response to atypical symptom is unpredictable. If there is good response, treatment should be prolonged and evidence suggests that the double dose should be prescribed for periods of up to 2-3 months.84 If there is no improvement in 3 months, the symptoms are most likely secondary to another cause and diagnosis should be reconsidered.

No evidence supports the use of prokinetics in patients with laryngopharyngeal reflux, whether combined with a PPI or as monotherapy. A recent systematic review, including only 4 high quality studies to be analyzed, determined that there was a high risk for bias due to the heterogeneity with which laryngopharyngeal reflux was defined.

In patients that present only with supposed atypical manifestations of GERD, a monitoring test, such as an impedance-pH study, is recommendable before administering PPI treatment.85 If there is no abnormal esophageal exposure to acid or positive symptom association, GERD is ruled out as the cause of extra-esophageal symptoms and the patient should be re-evaluated.

Patients categorized as having PPI failure or refractory GERD according to Figure 3 should be re-evaluated to rule out other causes that could explain their symptoms.

If the patients persist with typical symptoms, endoscopy is recommendable to rule out entities that include eosinophilic esophagitis and organic dyspepsia, among others, and thus reconsider treatment.12,86 If endoscopy is negative, manometry should be carried out and then an esophageal impedance-pH monitoring study while the patient is taking a PPI.12,85 Based on this study, there are 3 possibilities (Fig. 5):

• 1.

  Persistence of abnormal esophageal exposure to acid: in these cases a change of PPI, dividing or increasing the dose, or adding a nocturnal dose of H2RA can be recommended.

• 2.

  Esophageal exposure to normal acid, but positive symptom association with non-acid reflux: baclofen (not available in Mexico) is indicated in these cases, and although still controversial, some studies suggest surgical treatment could be beneficial.72,73,87,88

• 3.

  Negative study (with no evidence of acid or non-acid reflux): GERD is ruled out as the cause of symptoms in these cases and they are classified as functional heartburn. Visceral analgesics and other neuromodulators, such as amitriptyline, desipramine, citalopram, and venlafaxine are indicated.89

Figure 5.

Management of PPI failure or refractory GERD.

EoE: eosinophilic esophagitis; H2RA: histamine-2 receptor antagonists; ORL: Otorhinolaryngology; PPI: proton pump inhibitor.

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If the patients persist with atypical symptoms and there is no improvement, they should be reevaluated by a specialist in otorhinolaryngology, pneumology, allergology, or psychiatry, depending on the case. If a pH study was not carried out during the initial evaluation of the case, it is important to perform one without treatment, and depending on the result, reconsider the treatment. If the pH study is negative, GERD can be ruled out as the cause of the symptoms, but if the study is positive, then the PPI should be changed or the dose divided or increased.

BE is a premalignant lesion of the esophagus that is defined as the replacement of the squamous epithelium of the distal portion of the esophagus with columnar epithelium of any length, suspected by its endoscopic appearance and corroborated by a histopathology study reporting complete intestinal metaplasia.90,91

GERD is the most important pathogenic factor for the development of BE and its prevalence in GERD patients varies from 10 to 15%. Additional factors such as race, age, male sex, smoking, obesity, and hiatal hernia, among others, also play a significant role.92

The intentional search for BE through endoscopy is justified in subjects that have various risk factors: men above 50 years of age, a history of GER symptoms of long progression (more than 5 years), especially if the patient presents with obesity or overweight.91,93

Just having symptoms of GER is not sufficient justification for performing endoscopy in the search for BE. Despite the fact that a considerable number of the adult population complains of reflux symptoms, only a small number of them develop BE. The prevalence of BE reported in the general population varies from 1.2 to 1.6%.94,95

Ideally, cases of BE should be treated by a specialist and preferably at a referral center. Despite the fact that at present there is not enough evidence to support medical or surgical treatment as a strategy for preventing the neoplastic progression of BE, PPIs should be used, preferably in a continuous regimen, to control reflux symptoms.

Endoscopic surveillance at established intervals in accordance with the presence and grade of dysplasia is recommended in all patients with BE. The diagnosis of dysplasia should be confirmed by a second pathologist or, if possible, the sample should be sent to an expert pathologist. Intense PPI treatment between follow-up endoscopies is highly recommendable.

The recommended strategies for endoscopic vigilance are (Table 4):

• •

  EB with no dysplasia: endoscopic surveillance with biopsy is recommended in the first year. If the patient continues with no dysplasia, endoscopy with biopsy should be performed every 5 years.

• •

  BE with low-grade dysplasia: endoscopy with biopsy directed at the site of dysplasia every 6 months. After 2 consecutive years with no dysplasia, the patient can return to the endoscopy regimen for no dysplasia.

• •

  BE with high-grade dysplasia: endoscopic or surgical resection based on the availability of resources and trained endoscopists or expert surgeons. If the patient is not a candidate for or does not accept resection, endoscopy with biopsy should be performed every 3 months.

The current endoscopic BE treatment recommendation is endoscopic mucosal resection of the visible lesions and/or radiofrequency ablation of the residual BE to prevent metachronic lesions or recurrent neoplasia, as well as patient follow-up with endoscopic surveillance.

Endoscopic ablation therapy with liquid nitrogen in spray (cryotherapy) has been shown to be efficacious in small studies and has been proposed as alternative therapy for treating high-grade dysplasia in BE patients, but is not presently recommended as first-line therapy.

Today, the 2 clinically available methods for managing uncomplicated GERD are radiofrequency ablation (Stretta) and endoluminal fundoplication with EsophyX. The effectiveness of these methods has not been well confirmed and they should not be recommended in all patients.

• a.

  The initial treatment of choice for managing esophageal strictures due to reflux is endoscopic dilation with plugs or balloon.

• b.

  There is no evidence of a clear advantage in using plug dilation or balloon dilation for the management of esophageal strictures caused by reflux.

• c.

  The management of refractory or complex strictures can include the use of fully covered self-expandable metal stents or endoscopic radial incision of the stricture.

• d.

  Patients that receive endoscopic treatment of esophageal stricture due to reflux should also receive double dose, continuous PPI treatment.

Patients with an objective diagnosis of GERD can be considered for surgical treatment in the following cases:

• a.

  Patients that present with a reduced quality of life, persistent symptoms that cause problems, and/or disease progression despite adequate PPI therapy.96,97

• b.

  Patients with good PPI response, PPI-dependent, and with acceptable quality of life can be considered for surgery if they wish to have it. The patient must be informed as to the potential side effects and possible risks of the surgery.98,99

• c.

  Anti-reflux surgery can improve quality of life in certain patients with NERD.100,101

• d.

  Patients with extra-esophageal symptoms that have positive symptom correlation and good PPI response can benefit from anti-reflux surgery.102–105

• e.

  Patients with GERD and obesity can benefit more from bariatric surgery, such as gastric bypass, than from anti-reflux surgery. Indications are based on body mass index and bariatric surgery criteria.106,107

• f.

  Patients with large hiatal hernia (> 5cm).

• g.

  Patients with aspiration pneumonia

Novel devices, such as the LINX and EndoStim, are currently being evaluated and have shown promising results. However, more comparative, long-term studies are required to determine their place in GERD treatment.108–111

Heartburn is a frequent symptom during pregnancy and its main etiologic factor is the hormonal effect of progesterone. Complications of GERD during pregnancy are not common and therefore the routine performance of diagnostic studies, such as endoscopy, is not indicated.

Treatment should be carried out in ascending order, beginning with lifestyle and dietary modifications. First-line drug management should be based on antacids and sucralfate. If symptoms persist, an H2RA can be included. However, nizatidine should not be used, given that there have been reports of spontaneous abortions and congenital malformations in laboratory animals, leaving PPI use for untreatable or complicated symptoms and preferably from the second trimester of gestation. The FDA considers all PPIs class B drugs, except omeprazole, which is considered class C.112–114 In general, prokinetics are not recommended for GERD treatment, and so their use during pregnancy should be oriented toward the management of difficult-to-control nausea and vomiting, specifically with metoclopramide, categorized as a class B drug by the FDA.115

The aims of GERD treatment in persons above 65 years of age are essentially the same as those in patients below that age. Prevalence is difficult to establish, given that there are few studies specifically conducted on this age group and the concomitant diseases and other treatments hinder both the diagnosis and treatment of these patients. In general, frequency and symptom intensity in relation to heartburn and regurgitation are lower in patients above the age of 65, but complications of GERD, such as bleeding, stricture, or BE as primary manifestations of the disease are frequently found.

PPIs are the first-line treatment in any of the clinical presentations of GERD in this group of patients. The recommended doses are the same and it should be kept in mind that treatment will very likely be continuous. Special care must be taken in relation to PPIs that compete with other medications that have hepatic metabolism at the P450 cytochrome level, such as warfarin, phenytoin, theophylline, benzodiazepines, and calcium channel blockers. It appears that omeprazole and esomeprazole are the PPIs that compete the most for the hepatic metabolism site and so they should be used as little as possible.116