GORD is defined as "the presence of symptoms or complications that are directly related to the retrograde flow of gastric contents into the oesophagus."³

Despite the subjective limitation of epidemiological studies being based on symptoms alone, the increasing incidence not only adversely impacts on quality of life, but carries societal consequences such as impacting work productivity.¹

Pathophysiology

GORD and the digestive system

Under normal circumstances, the passage of food into the stomach occurs as shown in Fig. 1⁴

The anti-reflux barrier

The anti-reflux barrier in the stomach comprises of the lower oesophageal sphincter (LOS/LES) and the crural diaphragm and its function is kept under control by the supporting structures of the gastro-oesophageal flap valve.³ Under normal circumstances, this barrier protects the oesophagus against reflux of gastric acid and gastric contents.³ The LOS is a short segment of contracted smooth muscle at the distal end of the oesophagus; its resting tone varies among healthy individuals relative to intragastric pressure. This typically provides a sufficient barrier to counteract the gastrooesophageal pressure gradient across the oesophagogastric junction, preventing reflux.³

Gastric juice or gastric refluxate is a caustic mixture of acid, bile, and digestive enzymes that aid the digestion of food. ³ Although acid is the main cause of injury and irritation to the oesophagus during a reflux event, pepsin (even in small amounts) also contributes to oesophageal injury. In addition, bile acids further contribute to injury by disrupting the structure and functioning of the mucosal barrier, leading to severe oesophagitis.³ When the optimal functioning of the components of the anti-reflux barrier is impaired, reflux occurs, which pushes gastric acid and gastric contents (refluxate) into the oesophagus leading to symptoms of GORD as shown in Fig. 2³.

The reflux mechanism

One of the main mechanisms causing reflux is transient LOS relaxation, which accounts for 90% of reflux events in GORD without hiatus hernia.³ The time of exposure of the oesophageal mucosa to the refluxate is known as the reflux exposure time or bolus contact time, during which injury and inflammation of the mucosa and symptoms occur.³ After reflux occurs, peristaltic actions help clear refluxate from the oesophageal mucosa (oesophageal clearance). The presence of saliva offers a degree of buffering from the acid due to its bicarbonate content. In addition, saliva contains epidermal growth factor which assists with mucosal repair and protection. As such the two significant contributors to prolonged reflux exposure time and acid clearance are dysfunctional peristaltic action and impaired saliva production. In addition, the presence of a hiatus hernia can also impair acid clearance.³ The duration of gastric acid exposure of the oesophagus and the caustic nature of gastric acid determines the extent of oesophageal injury and symptoms.³

Predisposing and risk factors of GORD

The following table highlights the risk factors that may predispose patients to GORD.

Symptoms

The two characteristic symptoms of GORD are heartburn and acid regurgitation.^{1, 7}

Heartburn is described as a burning sensation in the retrosternal area that radiates into the chest and toward the neck, throat and, in some cases, the back. Heartburn is usually experienced after a meal, especially after a large fatty meal or after consuming spicy food. The feeling of heartburn may be intensified on lying down or bending over. Quality of life is impacted as heartburn at night time may cause interrupted sleep patterns and affect functioning the following day. The degree of oesophageal damage from GORD is independent of the frequency and severity of heartburn.⁷

Regurgitation is the perceived flow of refluxed gastric contents into the mouth or oesophagus.⁷

Less common symptoms of GORD include: dysphagia, chest pain, water brash, odynophagia, burping, hiccups, nausea and vomiting.⁷

One of the challenges in managing GORD is the considerable overlap between symptoms of GORD and other syndromes such as eosinophilic oesophagitis, functional dyspepsia and gastroparesis.⁷ Dyspepsia is a pain or feeling of discomfort in the upper abdomen and is just as common a complaint as GORD, but not usually associated with GORD. It is often difficult to differentiate between the two as one-third of patients with dyspepsia complain of regurgitation and heartburn.⁷

When this process of reflux happens on a continuous basis, the lining of the oesophagus becomes inflamed and is at risk of complications.⁶

The main complications of GORD include dysphagia, bleeding from erosive oesophagitis and oesophageal cancer.⁷ Dysphagia is regarded as a warning sign for patients with GORD and should be investigated further with endoscopy. Patients with a long-term history of heartburn usually suffer with dysphagia which is caused by peptic stricture and severe inflammation. Chest pain may occur from GORD but may be difficult to differentiate from that of cardiac pain.⁷

Other complications such as oesophageal ulcers, narrowing of the oesophagus and precancerous changes to the oesophagus, a condition known as Barrett's oesophagus can also occur.⁶

Assessment and diagnosis

Typical symptoms of heartburn and regurgitation experienced two or more times a week form the basis of a presumptive diagnosis of GORD.^{1, 5, 8} In addition, a positive response to the initial course of a proton pump inhibitor (PPI) serves as a confirmation of diagnosis.⁵ A negative response does not explicitly exclude GORD but may be suggestive of other diagnoses.⁸

In patients who do not respond to the PPI trial, or have warning signs or other chronic symptoms, further investigations may be required.⁸

Further investigations

Endoscopy

Endoscopy is primarily used to investigate complications and assess differential diagnoses.⁸ Although endoscopy is the method of choice in assessing tissue damage, it is invasive, expensive and may be normal in up to 70% of people,⁵ and as such should be limited to specific situations (refer to indications box).⁸ Approximately two-thirds of patients with symptoms of reflux will demonstrate normal endoscopic results. In these cases as well as in patients with ongoing symptoms, repeat endoscopy is not recommended, unless new warning signs are raised.^5-8

In addition to the warning signs, the following are indications for endoscopy in GORD:⁸

Barrett's oesophagus (BE) screening

BE results from inflamed oesophageal lining which in turn wears away, when GORD occurs on a continuous basis.⁶ To date, it is the only complication of GORD with potential for malignancy.¹ According to NICE guidelines, screening for BE may be considered in patients with individual risk factors such as:⁵

• Previous oesophagitis
• Long duration of symptoms
• Hiatus hernia
• Oesophageal stricture or ulcers
• Male patients
• Worsening of frequency of symptoms

Oesophageal pH studies

This 24-hour, catheter-based pH investigation is limited to patients who do not respond to treatment or undergoing assessment for anti-reflux surgery.^s,s

Helicobacter pylori infection

Epidemiological studies have demonstrated a lack of association between H. pylori and GORD as the presence of H. pylori has no effect on symptom severity, recurrence or efficacy of GORD treatment in most patients.¹

Management

The essential elements of GORD management are:¹

• Lifestyle interventions
• Reducing oesophageal luminal acid:
  • Local acid neutralisation
  • Medically suppressing gastric acid secretion
  • Anti-reflux surgery (rarely)

The goals of GORD management include:¹

• Achieve symptom relief
• Improve patients' health-related quality of life
• Aid oesophageal healing
• Prevent recurring symptoms
• Prevent complications

Lifestyle interventions

Patients with GORD must be educated and advised on the significant benefits of lifestyle changes on the improvement of symptoms.⁶

Weight management

Even a modest increase in weight is associated with an increase in GORD symptoms. Furthermore, weight gain increases the risk of erosive oesophagitis and BE.⁹

Weight loss has been shown to have the most significant impact on symptoms - a reduction in BMI of 3.5 kilograms per square metre (kg/m²) can reduce the risk of having frequent symptoms by 40%.⁸ In addition, a reduction in weight and waist circumference is associated with a lower incidence of symptoms of GORD, oesophageal acid exposure and reflux events after meals.⁹

Evidence suggests that weight loss directly reduces the pressure gradient and burden on the anti-reflux barrier.³

Dietary interventions

Although certain food groups may exacerbate symptoms of GORD, avoidance of these foods has shown to be of limited value.⁹ Nonetheless, identifying and avoiding trigger foods may offer symptom relief in some patients.^5,8

Sleeping position

Avoid eating meals two to three hours before bedtime and do not lie down soon after eating.^s,s

Elevate the head of the bed by approximately 20 cm.⁵ Compared to sleeping flat, sleeping with the head of the bed raised has been shown to reduce reflux events, aid acid clearance at a faster rate and reduce symptoms.⁹ Lying on the left side has shown shorter acid exposure time and faster acid clearance than sleeping on the right side. This is possibly due to the oesophagogastric junction being above the level of pooled acid when lying on the left side.⁹

Cigarette smoking and alcohol consumption

Cigarette smoking and alcohol consumption have been associated with an increase in reflux symptoms. Although there is a lack of evidence that cessation of smoking and alcohol use reduce the incidence of GORD symptoms, there are many health benefits associated with these interventions, including reducing the risk of oesophageal cancer.⁹

The goals of lifestyle interventions are for the patient to become symptom-free and resume optimal quality of life.¹

Pharmacotherapy-based Acid Suppression

Based on high-level evidence, acid suppression is considered to be the first-line treatment for GORD.³ Despite bile acids and pepsin being important contributors to oesophageal damage and reflux symptoms, treatments targeting these components are lacking.³

Proton Pump Inhibitors (PPIs)

PPIs form the foundation for the treatment of GORD⁹ and are the most effective drug class for the treatment of GORD, because they offer the most potent suppression of gastric acid secretion.^8,10 In South Africa, the following PPIs are available: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole.¹⁰

Gastric acid is secreted by the parietal cells in the stomach. The parietal cells have been the target for drug development for inhibition of acid secretion. The two major targets in the parietal cells are the histamine-2 (H₂) receptors, and the gastric H⁺, K⁺-ATPase enzyme which is known as the "acid pump" and comprises the final step in gastric acid secretion.^11,12 Hydrochloric acid is secreted by the parietal cells via the H⁺, K⁺-ATPase enzyme in response to acetylcholine, gastrin or histamine.¹² Aimed at the H₂ receptors, histamine-2 receptor antagonists (H₂RAs) have successfully improved healing rates of peptic ulcer disease.

However, H₂RAs have had little impact on symptoms of GORD as they have limited impact on pH control in the stomach.¹¹ This could be attributed to only blocking one of the receptor sites in the gastric acid process, while PPIs inhibit the "acid pump", which is regarded as the terminal stage of gastric acid secretion.^11,12 PPIs are prodrugs, activated by acid and work by binding to and inactivating the "acid pump" or proton pump (H⁺, K⁺-ATPase).^8,11

While PPIs do not reduce the number of reflux events and do not have any impact on the pathogenesis of GORD, they work to neutralise the pH of the refluxate, making it less acidic or more alkaline.⁹ Since PPIs are effective only when the proton pumps in the stomach are active, i.e. in the postprandial period and due to their short half-life (1-2 hours), the timing of administering the PPI is crucial for maximum benefit to the patient.⁸ Treatment with the PPI should be initiated as a once-daily dose, 30-45 minutes^8,9 before a meal to ensure the maximum concentration of PPI at the time of the meal. Since the highest amount of H⁺, K⁺-ATPase is present after a prolonged fast, the dose should be given before breakfast.⁸ Evidence suggests that the available PPIs are comparable in efficacy. The agent of choice is thus influenced by cost, potential for interactions and side effects as well as personal preference.^8,10

According to the World Gastroenterology Organization (WGO), the recommended daily doses of available PPIs for GORD are as shown in the table below:¹

Histamine-2 receptor antagonists (H₂ RAs)

H₂RAs manage symptoms of GORD by blocking the action of histamine at the H₂ receptors in the parietal cells of the stomach. As a result, gastric acid secretion is reduced.¹⁰ H₂RAs are mainly used as a "step-down" treatment for patients with uncomplicated GORD who have responded to PPI therapy and are in remission.⁹ In South Africa, cimetidine and ranitidine are available.^{6, 10} Since cimetidine binds to microsomal cytochrome P450 in the liver and inhibits oxidative hepatic drug metabolism, there is potential for multiple drug interactions involving other drugs metabolised by the cytochrome P450 pathway.¹⁰ Ranitidine has a lower potential for drug interactions as it does not bind to cytochrome P450.¹⁰ While nocturnal acid suppression can be successfully managed with supplemental H₂RAs given at bedtime, there is a risk of tachyphylaxis developing within seven days.⁹

Reflux-reducing agents

Baclofen, which is a gamma-amino butyric acid B receptor agonist, has demonstrated a reduction in transient LOS relaxations and reflux events. Although these results are promising, side effects of baclofen may limit its use. In cases of persistent symptoms (without complications) despite PPI therapy, baclofen may be considered as a treatment option.⁹

Antacids, surface agents and alginates

These adjunct medicines are available over-the-counter in tablet or liquid form and are usually helpful for heartburn, which is usually the initial symptom described by patients with GORD:⁶

• Antacids offer effective and rapid symptom relief of short duration (approximately two hours) by neutralising the gastric pH, which in turn reduces the exposure of the oesophageal mucosa to gastric acid during reflux.^{6, 10} Antacids usually contain a combination of magnesium, aluminium or carbonate compounds.⁶
• It is recommended that antacids be taken an hour after meals and at bedtime. Tablet formulations are most convenient when additional doses are needed.¹⁰
• Antacids may affect the absorption of drugs such as tetracyclines, iron, digoxin and indomethacin. A minimum of a 2-hour interval between doses of antacids and other oral medication is recommended to reduce the risk of drug interactions.¹⁰
• Sucralfate, a surface agent, forms a physical barrier between the stomach and the oesophagus by adhering to the mucosal surfaces and protecting them from injury.⁶
• Alginates prevent the reflux of stomach contents into the oesophagus by forming a viscous gum that floats within the stomach.⁶

Management approach

Patients experiencing heartburn less than twice per week usually respond to OTC antacids or alginate therapy. These patients should be advised on lifestyle and diet modifications, steps which usually improve symptoms of heartburn.¹

A diagnosis of GORD forms the basis for initiating treatment with a PPI, as per the figure below:⁸

Managing GORD - Prioritise treating symptoms

Patients with symptoms characteristic of GORD who respond to initial PPI treatment may be offered the "when needed" approach to PPI dosing, while maintaining lifestyle interventions. It is expected that patients experience a period of hyperacidity when the PPI is withdrawn. However, symptoms usually lessen over a period of approximately one month. Any symptoms that recur may be due to an underlying reflux disease. Using PPls when required provides adequate efficacy for some patients with GORD. However, the rate of relapse over six months is between 75-90%. This high relapse rate does not indicate treatment failure, but rather highlights the chronic nature of GORD. As mentioned previously, gastroscopy is not indicated in patients with GORD (without warning signs).⁸

Another approach to managing GORD is a step-down of PPI where the dose is reduced to determine the lowest dose needed to keep symptoms at bay, while maintaining lifestyle interventions.⁸

Treatment challenges

Persistent or refractory reflux symptoms

These occur in approximately 20-30% of patients who do not respond to the acid suppressive ability of PPI treatment. In some of these cases, the diagnosis should be reviewed as conditions such as delayed gastric emptying, functional dyspepsia and oesophageal hypersensitivity are often mistaken for GORD. Other factors influencing response to PPI treatment include compliance and administration issues. Patient compliance is usually poor and contributes to at least half of all cases in which symptoms persist. A lack of understanding of the pharmacokinetics of PPls often leads to patients being incorrectly instructed about when to take doses.⁸ Intensification of acid suppression includes increasing the PPI dose to twice a day or switching to a different PPI. The addition of a night-time dose of a H₂RA or using a surface agent such as sucralfate may further intensify treatment. To avoid the nocturnal tachyphylaxis caused by H₂RAs, a regimen of two weeks on and two weeks off is recommended.^{5, 8}

Rebound hyperacidity

Although PPls are the first-line treatment for GORD, PPls may be the cause of recurrent reflux or rebound hyperacidity. The acid suppression from PPls results in hypergastrinaemia, which causes an increase in parietal cell mass in the stomach. The result is a hypersecretion of acid when PPls are no longer used, which can last for many weeks. This often leads to repeat PPI use and dependence. Efforts to prevent this from occurring include slowly weaning the patients off PPI therapy by reducing their dose and using step-down therapy with H₂RAs or even adjunct alginate therapy.⁵

On the horizon - future prospects

In light of PPls being successful in treating GORD, little has been done in the development of "newer" treatment options for GORD in the past decade. The focus and interest has been in optimising PPI use and encouraging lifestyle interventions. However, the following recent pharmacologic developments have been investigated:⁹

• Potassium-competitive acid blockers (P-CABs) have demonstrated inhibition of acid secretion by inhibiting the proton pump in a potassium ion competitive mechanism. In a clinical study, vonoprazan was the first P-CAB demonstrating that a 20 mg dose healed 99% of patients with erosive oesophagitis over an 8 week period, compared with lansoprazole (95.5%). The safety of this drug still needs evaluation owing to the increase in gastrin being reported and the unknown significance thereof.⁹
• An investigational drug, IW-3718, is a gastric retentive formulation of a bile acid sequestrant, being evaluated as an add-on therapy to patients who have a sub-optimal response to PPls.⁹

Understanding the pathogenesis of GORD is a topic of ongoing research. The effect of the microbiome on the development of gastrointestinal diseases has sparked interest in its possible role in GORD. Preliminary studies have associated changes in the oesophageal microbiota with GORD. However, these findings need further studies and research to confirm the role of the microbiome in GORD specifically.³

Conclusion

Although GORD is a common gastrointestinal complaint, understanding its pathophysiology is complex and driven by multiple factors.³ Defined by symptoms of heartburn and regurgitation that affect quality of life, GORD (without complications) can be managed through lifestyle initiatives and acid suppression therapy. Up to one-third of patients can be managed in this manner. Up to 15% of patients are able to discontinue their medication completely.⁹ Nonetheless, a substantial proportion of patients require long-term acid suppressive therapy.

While PPls offer the most successful first-line treatment of GORD, PPls do not address the primary causes of reflux.⁵ Ongoing research to improve understanding of the pathophysiology of GORD is directed at developing novel or improved targeted treatment options for patients with GORD.³

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