Gastroesophageal reflux disease

GORD (UK) or GERD (US) is by far the most common oesophageal disorder and usually arises from excessive exposure of the distal oesophagus to gastric contents (acid and/or bile). Presentation can be with obviously digestive symptoms (e.g. heartburn, dyspepsia) or with extra-oesophageal manifestations (e.g. hoarseness, cough). The history is pivotal for diagnosis because of the extremely high prevalence of reflux-induced symptoms and the lack of a definitive, inexpensive diagnostic test. A trial of acid-suppression therapy can be used as an aid to diagnosis, with endoscopy the first choice test when investigation is required. Proton pump inhibitors are the mainstay of treatment.

Management should be tailored to the severity, which may vary considerably.

Definition

Some reflux of gastric and duodenal contents into the oesophagus occurs in everybody due to vagally mediated transient lower oeophageal sphincter relaxations. It should only be considered a disease when it gives rise to symptoms or complications sufficient to impair quality of life. Pathogenic reflux may occur without causing mucosal damage. The terms reflux or peptic oesophagitis should be reserved for circumstances when endoscopy demonstrates that the oesophageal mucosa is clearly breached by the action of the refluxed gastric contents. Minor changes such as erythema, oedema, or friability have been shown to be very unreliable indicators of the presence of oesophagitis. The disease can be further classified into oesophageal and extra-oesophageal syndromes using the Montreal classification.

Aetiology

In most patients reflux disease arises from the excessive exposure of the distal oesophagus to gastric contents which are primarily acid and/or bile. This is usually because of an abnormal frequency or duration of reflux episodes. In a few patients, however, symptoms arise with relatively normal levels of acid exposure, presumably because of sensitization of the oesophageal mucosa. In normal individuals excessive reflux is prevented by the lower oesophageal sphincter and an external sphincter formed by the crural diaphragm. Pathological reflux generally occurs as a result of defective neural control of the lower oesophageal sphincter. Hiatus hernia is common in patients with reflux disease and causes displacement of the sphincter from the hiatus formed by the diaphragmatic crura. Most reflux occurs during the day, usually after food, but lying down will ameliorate the antireflux effect of gravity and nocturnal reflux can be a disabling symptom. Refluxate is cleared from the oesophagus by peristalsis and swallowed saliva. Slow clearance of oesophageal acidification contributes significantly to prolonged acid exposure in about 50% of patients. This can be an important contributor to severe gastro-oesophageal reflux disease in systemic disorders such as scleroderma which affect gut motility.

Risk factors for gastro-oesophageal reflux disease include heritability (up to 30% of the risk), obesity, and age but not gender. Alcohol and smoking may play a role. Asthma increases the risk as do medications which relax the lower oesophageal sphincter such as calcium channel antagonists, nitrates, anticholinergics, and methyl xanthines.

Consequences of excessive reflux

Symptoms

These are an important source of disability. Evidence suggests that heartburn occurring on more than 2 days a week causes significant impairment of quality of life. However, presentation may be with the less specific symptom of dyspepsia (or epigastric discomfort), belching, nausea or with regurgitation, and dysphagia due to either stricture or motor dysfunction of the oesophageal body. There are a number of extra-oesophageal manifestations of reflux including respiratory symptoms such as hoarseness, persistent cough, and asthma. Chronic sinusitis, otalgia, and glue ear may also be associated with reflux.

Complications of reflux disease

The chemical insult from excessive exposure of the mucosa to gastro-duodenal contents leads to distal oesophageal erosion or ulceration in between 40 and 60% of patients with troublesome reflux symptoms and columnar-lined (Barrett’s) oesophagus in between 5 and 10% of individuals, as discussed in detail below. The extent of ulceration varies greatly, from tiny patches of erosion to extensive circumferential ulceration in a small minority. Peptic stricture sufficient to cause dysphagia is typically only associated with severe oesophagitis. When strictures are severe this may lead to malnutrition. Bleeding from oesophagitis may occur but is rarely life-threatening except when it occurs from a deep ulcer associated with columnar metaplasia.

Diagnosis and assessment of severity

History

The history is pivotal for diagnosis because of the extremely high prevalence of reflux-induced symptoms and the lack of a definitive, inexpensive diagnostic test for reflux disease. A trial of acid-suppression therapy can be used as an aid to diagnosis.

Endoscopy

When investigation is required, endoscopy is the first choice as it is the only test that can give sensitive recognition and grading of oesophagitis (e.g. Los Angeles classification system) and reliable diagnosis of oesophageal columnar metaplasia (Barrett’s oesophagus). Endoscopy also allows for the effective identification of significant peptic strictures, other types of oesophagitis (discussed below), and peptic ulcer disease as well as malignancies. The value of endoscopy as the initial investigation is greatly enhanced by the accurate diagnosis of endoscopic biopsy and, where indicated, cytology brushings. As discussed above, however, most patients with reflux disease do not have endoscopically visible mucosal damage, so a negative endoscopy does not exclude the diagnosis of reflux disease (so-called nonerosive reflux disease).

Oesophageal function tests

Oesophageal manometry and ambulatory 24-h pH monitoring have a limited but important role in the diagnosis of reflux disease. Oesophageal pH monitoring is most useful in patients with troublesome symptoms but without endoscopic signs of oesophagitis in whom a trial of therapy has failed, and patients with atypical symptoms that cannot be clearly related to reflux. Patients with suspected reflux symptoms but with no endoscopic evidence of oesophagitis who are being considered for antireflux surgery should also undergo oesophageal pH monitoring.

Recently, multichannel oesophageal impedance monitoring has been shown to distinguish between swallowed or refluxed fluid and gas, although at present its use is mainly confined to the research setting. Combined with pH monitoring, it may identify individuals with ‘nonacid’ who fail to respond to treatment. Bile reflux can be assessed using Bilitec probes, but these are not routinely available anywhere.

Barium swallow and meal

This is an inappropriate primary diagnostic test; it is of no value for the detection of abnormal reflux, and is insensitive for the diagnosis of oesophagitis and cannot grade it. Other pathologies such as gastric ulcer and oesophageal stricture are demonstrated with reasonable sensitivity, but adequate evaluation of these findings requires endoscopic biopsy. However, barium swallow is the best method for recognizing extrinsic oesophageal compression which may be producing symptoms that could be interpreted as being due to reflux, and in the assessment of an anatomically complex hiatus hernia. The mere demonstration of hiatus hernia, however, does not necessarily indicate the presence of reflux disease.

Principles of management

The major aims of treatment are to provide adequate symptomatic relief and control of oesophagitis. Reduction of oesophagitis to minor patchy erosions is probably sufficient to prevent the complications of oesophagitis, although adequate symptomatic relief is usually achieved only when oesophagitis is completely healed.

Tailoring and titration of therapy

The severity and frequency of symptoms and the endoscopic findings should be used to choose an appropriate level of initial therapy. There is some debate about whether to treat patients with a high or low dose of acid-suppressant drugs initially. An initial trial of low- to medium-dose empirical therapy has the disadvantage of giving less precise diagnostic information, and often gives only slow relief of symptoms. Patients with severe oesophagitis will usually not respond adequately to low dose acid-suppression. Initial high-dose proton pump inhibitor therapy is likely to give more immediate confirmation of the diagnosis and prompt relief of symptoms. For optimum cost-effectiveness and to reduce complications high dose treatment should be followed by a step-down approach to long-term therapy.

Nondrug measures and antacids

The most useful measures are avoidance of large meals and provocative foods, drinks, and physical activities. The benefits to reflux disease of stopping smoking, weight loss, and elevation of the bed head are uncertain. Antacids will not usually prevent symptoms, but may be effective in aborting episodes of heartburn. These low-cost measures are worth a trial in patients with mild intermittent symptoms and should be used as maintenance therapy if they prove effective, provided that their impact on lifestyle is acceptable to the patient.

Acid suppression

Inhibition of secretion of gastric acid makes gastric juice less injurious but does not stop reflux. This has deservedly become the most widely used drug therapy because of its high efficacy and adjustability. Proton pump inhibitors are the mainstay of treatment because of their effectiveness in reduction of food-stimulated acid secretion and their greater overall efficacy in control of acid secretion compared with histamine-2 receptor antagonists. However, histamine-2 receptor antagonists can be a useful adjunct to proton pump inhibitors for controlling nocturnal reflux.

Long-term treatment with acid suppressants maintains patients free of symptoms and oesophagitis indefinitely, but withdrawal is usually associated with prompt relapse. The maintenance dose appears to be the same as the lowest effective healing dose. There have been concerns about the safety of long-term acid suppression ever since the introduction of istamine-2 receptor antagonists. To date, follow-up of patients treated continuously for 10 years or more with acid suppression has shown no evidence of any effects of significance, but in the context of patients who may require treatment with these agents for decades, more extensive follow-up is still needed. Given these theoretical safety considerations and also drug cost, long-term treatment of reflux disease with these agents should use the lowest effective dose. In some patients use of proton pump inhibitors is limited by side effects such as diarrhoea and patients on long-term therapy may be prone to increased gastrointestinal infections due to loss of the antimicrobial effects of low gastric pH.

Motility stimulants

The best researched, most efficacious motility stimulant is cisapride, which is a parasympathomimetic that acts as a serotonin 5-HT4 receptor agonist. It mainly acts through enhancing oesophageal acid clearance as well as increasing muscle tone in the lower oesophageal sphincter. Unfortunately, cisapride can have effects on cardiac conductance that may rarely lead to sudden death at peak serum levels, especially when various drugs are co-administered. Cisparide has therefore been withdrawn from the market in many countries and should only be used cautiously in severe cases. Alternative prokinetics such as metoclopramide and domperidone may be useful adjuncts, again when used in combination with acid-suppression therapy.

Endoscopic antireflux procedures

Techniques include endoscopic suturing, radiofrequency energy delivery to the lower oesophageal sphincter, and submucosal prosthetic implants. Effectiveness has mainly been assessed in uncontrolled trials without long-term follow-up data. There is no place for such therapies outside clinical trials at present.

Antireflux surgery

In skilled hands, antireflux surgery is a very effective long-term therapy. Negative factors are the dependence of the results on the expertise of the surgeon and the morbidity and small (approximately 0.5%) mortality associated with the surgery itself. Laparoscopic antireflux surgery (usually a Nissen fundoplication) is a major advance, as it achieves good control of reflux with a major reduction in the morbidity inherent in the more traditional approach.

Choice between medical and surgical therapies

Selection of a medical or surgical therapy should take account of the severity of disease and the risks of antireflux surgery specific to the patient. It should also take account of the patient’s age, both from the point of view of operative risk and the time over which the patient will need treatment for reflux disease, the cost of effective medical therapy, and, naturally, the preferences of the patient. The choice between medical therapies should be largely governed by the local cost of the alternatives that give the necessary level of treatment, as all of the first-line options are effective, safe, and well tolerated.

Management of complications of reflux disease

The important complication of oesophageal columnar metaplasia (Barrett's oesophagus) is discussed in a separate section below.

Peptic stricture

Dysphagia secondary to stricture formation needs to be distinguished from the more common dysphagia seen in patients with reflux disease which is due to defective triggering and control of oesophageal body peristalsis (see the section on nonspecific oesophageal motor disorders, below). Peptic stricture is managed by a combination of peroral dilatation and healing of oesophagitis by either medical or surgical means. All strictures should be treated as malignant until proven otherwise by repeated biopsy. Provided oesophagitis is healed, stricture is usually not an ongoing problem.

Respiratory complications

Respiratory disease may occur either as a result of direct aspiration of refluxed gastric contents or from the reflex effects of gastro-oesophageal reflux. It is difficult to prove that reflux disease which coexists with respiratory disease is actually the cause of the respiratory problem. The best investigative approach is probably a trial of high-level acid inhibition with at least a double dose of proton pump inhibitor and prokinetics for at least 2 months. Management of respiratory disease by antireflux surgery is not guaranteed to be successful.

Regurgitation

Voluminous regurgitation is the main symptom in a small subgroup of patients with reflux disease. They may present complaining of vomiting, but a detailed history reveals that there is no prior nausea, and no effort involved in the appearance of the gastric content in the mouth. The determinants of high-volume reflux and regurgitation have not been defined. Treatment with proton pump inhibitors and prokinetics can have substantial benefits, but in more severe cases antireflux surgery is usually the only effective management.

Noncardiac chest pain

Reflux is also an important cause of noncardiac chest pain (see below).

Oesophageal columnar metaplasia (Barrett's oesophagus)

Definition and nomenclature

Oesophageal columnar metaplasia (Barrett’s oesophagus) is defined as the conversion of the normal stratified squamous epithelium with a columnar-lined mucosa which may have characteristics of gastric or intestinal epithelium. The lack of international consensus on the definition of this disease has led to confusion in the literature. However, it is widely accepted that it is the subtype characterized by intestinal metaplasia with goblet cells which has the highest risk for malignant progression and in many countries the term Barrett’s oesophagus has been restricted to this subtype. The extent of the metaplasia may vary from 1 cm to the entire oeosophageal length and there appears to be a correlation between the length of the segment and the proximal extent of reflux exposure. The metaplasia generally starts in the distal oesophagus although discrete columnar islands may occur. The accepted nomenclature for describing the endoscopic features is the Prague classification in which C indicates circumferential involvement in centimetres and M is the maximal disease extent in centimetres (e.g. C2,M5 for a 5 cm segment with 3 cm of metaplastic tongues).

Aetiopathogenesis

Columnar metaplasia occurs in the context of chronic gastro-oesopageal reflux, predominantly in white males. Its incidence appears to have increased, even taking into account the more frequent use of endoscopy, and the reasons for this are still under intense scrutiny. Possible explanations include an increase in obesity leading to an increased susceptibility to reflux and the reduced prevalence of Helicobacter pylori infection with a consequent increase in gastric acid secretion. Columnar metaplasia carries a 40-fold increased risk for the development of oesophageal adenocarcinoma compared with the general population, which equates to an annual incidence of 0.5 to 1%. Occurrence of adenocarcinoma is very strongly associated with prior development of high-grade dysplasia in the metaplastic segment and therefore endoscopic surveillance is generally advocated.

Management

Surveillance hinges on the subjective interpretation of dysplasia in multiple, random biopsies (usually quadrantic biopsies every 2 cm according to the Seattle protocol). The frequency of surveillance depends on the degree of dysplasia (Table 1 below). This arduous protocol has not been uniformly accepted since no data from randomized controlled trials support a reduction in population mortality from oesophageal adenocarcinoma using this approach. On the other hand, the outcome for individuals with symptomatic invasive adenocarcinoma is universally poor compared with surveillance-detected disease. Failure to discuss the risk for adenocarcinoma and the option of endoscopic surveillance with a patient who has oesophageal columnar metaplasia could well be viewed as an indefensible lapse of practice, despite the uncertainties about cost-effectiveness.

The treatment of high-grade intraepithelial neoplasia (dysplasia) in oesophageal columnar metaplasia is controversial. First, the diagnosis should be corroborated by two independent pathologists, preferably on biopsies taken at two separate endoscopies (Table 1). Increasingly, endoscopic mucosal resection can be used as a diagnostic adjunct to determine depth of invasion. This will inform management decisions and in some cases will turn out to be a therapeutic local excision. Endoscopic ultrasound may be useful but there is a danger of overestimating the depth of invasion. The management options will be determined by the extent of dysplasia and the fitness of the individual as well as local expertise. Oesophagectomy (which may be performed as a transhiatal or even a laparsocopic procedure with a limited lymph node resection) is still considered to be the gold standard management option although increasingly endoscopic ablation using photodynamic therapy, argon plasma coagulation, or more recently radiofrequency ablation are being offered. Some centres favour frequent continued surveillance until there is clear evidence of invasion. Lack of detailed knowledge about the natural history of high-grade dysplasia makes the decision-making process especially difficult. Discussion with a multidisciplinary team with expertise in oesophageal cancer is recommended as well as full consultation with the patient.

Barrett’s oesophagus may also be associated with deep benign oesophageal ulceration within the columnar-lined segment and strictures usually at the squamocolumnar junction. Occasionally ulcers can erode into mediastinal structures or the pleural space although this is encountered much less frequently with the ready availability of acid suppressants.

Table 1 Surveillance protocol for columnar lined (Barrett’s) oesophagus for patients willing and fit to undergo regular endoscopy
Histopathological diagnosis Endoscopy frequency Clinical management
  • Intestinal metaplasia
  • No dysplasia
2 years Treat heartburn symptoms with PPI
  • Intestinal metaplasia
  • Indefinite intraepithelial neoplasia/dysplasia
6 months after index finding. Annual if changes persist. Revert 2 yearly when 2 consecutive endoscopies no dysplasia Ensure adequate acid suppression to prevent inflammation confounding diagnosis
  • Intestinal metaplasia
  • Low grade intraepithelial neoplasia
6 months after index finding. Annual if changes persist. Revert 2 yearly when 2 consecutive endoscopies no dysplasia (caution if multifocal change) Ensure adequate acid suppression to prevent inflammation confounding diagnosis
  • Intestinal metaplasia
  • High grade intraepithelial neoplasia
Confirm diagnosis on second endoscopy with 1 cm 4-quadrant biopsy and assessment by two independent pathologists Consider endoscopic or surgical intervention—method depending on comorbidity and focality of lesion

Noncardiac chest pain

Definition

Implicit in this rather circuitous and negative label is the view that this pain has a cardiac-like quality, but there is no evidence for a cardiac origin. The oesophagus is the next most likely origin, but it is unlikely that all such pain arises from the oesophagus.

Aetiology

Evidence for triggering of pain by reflux or oesophageal motor dysfunction has been found in between one-fifth and one-half of patients evaluated. Oesophageal mucosal pain due to gastro-oesophageal reflux is the most common and helpful diagnosis. Frank oesophageal spasm associated with achalasia and diffuse oesophageal spasm is an unusual but convincing cause of noncardiac chest pain. In the majority of patients, most episodes of pain occur independently of reflux and any motor abnormality, although many of these patients have nonspecific oesophageal motor disorders or hypertensive peristalsis (see above). Sustained contraction of the longitudinal muscle has been identified by prolonged intraluminal ultrasonography in association with a high proportion of episodes of pain. Nevertheless, in many patients noncardiac chest pain appears to be a primary oesophageal hypersensitivity disorder and any motor disorder may be an epiphenomenon. Recent work to understand the neurophysiological basis for the hypersensitivity suggests that there may be distinct phenotypic subclasses of disease based on enhanced afferent transmission defects vs heightened secondary cortical processing.

Symptoms

By definition, the pain resembles cardiac pain in its sensation and distribution. It can be very intense and distressing, can disturb sleep, and may be worse during periods of emotional stress. Postprandial occurrence, in association with heartburn, suggests that it may be caused by reflux. When pain is associated with dysphagia, vigorous achalasia or oesophageal spasm are very possible.

Diagnosis

Myocardial ischaemia should first be excluded as the cause. Endoscopy should then be performed followed by oesophageal pH and motility studies when symptoms are disabling. Investigation can be unrewarding.

Treatment

Reassurance is essential to prevent repeated hospital admissions for fear of a cardiac cause. If the pain is triggered by gastro-oesophageal reflux, high-level acid-suppression therapy should be tried (see section on gastro-oesophageal reflux disease). Achalasia and diffuse oesophageal spasm should be treated on their own merits. In patients with no clear cut diagnosis, treatment with anxiolytics and antidepressants has been found to be moderately effective. Agents that reduce the strength of oesophageal contraction, such as calcium antagonists, appear ineffective in hypertensive peristalsis.

Gastroesophageal reflux disease - very detailed technical article

The diagnosis and management of invasive oeosphageal adenocarcinoma is discussed in the article titled:

Oesophageal cancer.