Gastro-oesophageal reflux disease

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The main goals of treatment are to control symptoms and to prevent complications. The basis of treatment is acid suppression.[1]

Most patients with GORD require prolonged pharmacotherapy with acid suppressants. Proton-pump inhibitors (PPIs) are the most effective drugs in this category and are the mainstay therapy for GORD.[63]

Several studies have highlighted risks associated with long-term use of PPIs; therefore, attempts to stop or reduce the dose to the minimum necessary to maintain symptomatic control should always be pursued.[64][65][Evidence C]What are the risks associated with long-term use of proton-pump inhibitors (PPIs) compared with no PPIs in people with gastro-oesophageal reflux disorder (GORD)?[64]

Diagnostic manoeuvres such as endoscopy help to determine appropriate treatment. Conversely, treatment with PPIs is often also diagnostic.

Management of mild and typical GORD

People with mild or infrequent cases of GORD often seek help after self-treatment with an antacid, H2 antagonist, non-prescription PPI (if available), or lifestyle changes.

Lifestyle changes

Recommended for all patients.[1][66] Measures include: weight loss for overweight people; smoking cessation for tobacco smokers; head-of-bed-elevation; and avoidance of late-night eating if nocturnal symptoms are present.[1][5][21][67]

Patients should avoid eating 3 hours before bedtime and sleeping on the right side.[5] Four to five small meals are preferred over two or three large meals.[5]

Specific food eliminations (e.g., chocolate, caffeine, alcohol, acidic and/or spicy foods) are not required unless selective changes provide individual benefit.[1]

One randomised controlled trial found that reducing the intake of simple sugars improved pH monitoring outcomes and GORD symptoms.[68]

Initial treatment with PPI

For patients who present with typical, regular heartburn and no alarm symptoms, treatment should be started with standard-dose PPIs for about 8 weeks in combination with lifestyle changes.[1][37] In the UK, the National Institute for Health and Care Excellence recommends initial PPI treatment for 4 or 8 weeks.[36]

It is recommended to start treatment with the lowest effective dose of PPI.[1][5][69] After achieving adequate symptom control, the PPI should be tapered to the lowest effective dose.[37] Most patients will need ongoing therapy.

PPIs reduce gastric pH most effectively when taken 30-60 minutes before meals.[1][5]

Inadequate response to initial therapy

If there is absent or inadequate response, treatment can proceed to high-dose PPI.[63] If it is not possible to use a high-dose PPI, some patients respond to switching the PPI. More than one switch of PPI is not recommended.[63]

Endoscopy is recommended for patients who do not respond to initial therapy.[63]

If endoscopy fails to show erosive oesophagitis or Barrett's oesophagus, further diagnostic testing should be considered. Patients with refractory GORD should be referred to a gastroenterologist for diagnostic testing.

Reasons for lack of response to therapy should be sought. These may include:

Functional GORD/hypersensitivity (patient does not have GORD by standard pH definition)
Non-adherence to treatment
Non-acidic reflux
Inadequate acid control, or
Zollinger-Ellison syndrome or individuals with polymorphisms in cytochrome P450 2C19 (CYP2C19) resulting in rapid metabolism of PPIs.[70]

Bedtime adjunctive use of an H2 antagonist may be considered in people with nocturnal symptoms or with pH-monitoring evidence of nocturnal oesophageal acid reflux, when PPIs are not completely effective.[1][37] However, tachyphylaxis may occur.

Management of atypical and complicated symptoms

Patients who present with complicated or atypical GORD (e.g., dysphagia or evidence of GI bleeding) usually have immediate endoscopy.[1]

Patients whose symptoms have lasted >5 years, or who are older than 40 years, also typically have endoscopy.

Patients with atypical or complicated symptoms are treated with a PPI, but not empirically.

Patients who have extra-oesophageal features (e.g., laryngitis, globus, tooth enamel erosion, halitosis) with typical GORD symptoms may have an initial 8-12 week trial of high-dose PPI therapy before endoscopy or further testing.[1][6] Empiric PPI therapy is not recommended for patients with isolated extra-oesophageal features.[6]

Duration of medical therapy

Patients who respond to therapy will often need long-term maintenance treatment.

Maintenance PPI therapy is recommended for those with:[1]

symptoms when the PPI is discontinued
erosive oesophagitis and Barrett's oesophagus.

Most patients relapse off PPI therapy. However, there are risks associated with long-term use of these drugs; therefore, attempts to stop or reduce the dose to the minimum necessary to maintain symptomatic control should always be pursued.[64][65][Evidence C]What are the risks associated with long-term use of proton-pump inhibitors (PPIs) compared with no PPIs in people with gastro-oesophageal reflux disorder (GORD)?[64]

Some people with non-erosive reflux disease (NERD) may be able to use on-demand or intermittent PPI therapy.[1] [ ]

Some experts recommend a trial of step-down therapy.[71][72]

Anti-reflux surgery

Surgery (e.g., open fundoplication, laparoscopic fundoplication, magnetic sphincter augmentation) is reserved mainly for people who have had a good response to PPIs, but who are non-adherent to therapy or do not wish to take long-term medical treatment (e.g., due to adverse effects). People who do not respond to PPIs pre-operatively are less likely to respond to surgery.[1]

Only a very small percentage of the GORD patient population undergoes anti-reflux surgery each year.[73][74] All patients should be involved in the decision to initiate anti-reflux surgery. Postsurgical complications occur in up to 20% of patients.[75]

US and European guidelines suggest that the choice of anti-reflux surgery procedure should be informed by surgical expertise and regional practice.[76][77][78]

Guidelines recommend the following preoperative assessments to establish the indication for surgery and to aid in patient selection:[1][77][78]

ambulatory pH monitoring, if there is no evidence of erosive oesophagitis
manometry, to exclude achalasia or scleroderma-like oesophagus.

Anti-reflux surgery compared with medical therapy

Meta-analyses of randomised controlled trials indicate that, in the short-term, GORD-related quality of life outcomes may be superior following surgery than medical treatment.[79][80]

Laparoscopic surgery appeared to be more effective than PPIs for improving heartburn and reflux in the short (<1 year) and medium (1-5 years) term; rates of dysphagia in the short and medium term were greater among people who underwent surgery.[79] [ ] Studies included in these meta-analyses had important methodological limitations.[79][80]

Laparoscopic anti-reflux surgery compared with open surgery

In one meta-analysis of 12 randomised clinical trials, laparoscopic anti-reflux surgery was associated with a significant reduction in duration of hospital stay, return to normal activity, and complication rates, compared with open anti-reflux surgery.[81] Operative time was longer, and need for further surgery higher, in the laparoscopic group. Findings from the meta-analysis are limited by poor-quality data, variation across trials, and publication bias.

A subsequent meta-analysis reported similar results.[82]

Long-term effectiveness of anti-reflux surgery

Long-term effectiveness of surgery is unclear; the benefits must be balanced against the risk of mortality and other adverse effects.[79][83] [ ] [Evidence C]

In one large retrospective cohort study, in which 2,655 individuals were followed for a median of 5.6 years following laparoscopic anti-reflux surgery, reflux recurrence (defined as need for acid suppressants for >6 months or repeat anti-reflux surgery) was reported in 17.7% of individuals.[84] Risk factors for reflux recurrence included: female sex, older age, and presence of comorbid conditions.[84]

Network meta-analysis of more than 50 randomised controlled trials indicates that posterior partial fundoplication may be the preferred surgical approach for management of GORD in adults.[85]Findings were consistent across all follow‐up time points (including medium- [1-5 years] and long‐term [≥10 years]).[85]

Obesity and anti-reflux surgery

Obesity is associated with an increased risk for recurrence of GORD symptoms in patients undergoing laparoscopic anti-reflux surgery.[86][87] Mean operative times are greater for obese patients.[86][88]

Obese patients considering anti-reflux surgery may be candidates for bariatric surgery.[1]

Endoscopic therapy

Endoscopic anti-reflux therapy may be considered for selected patients with uncomplicated GORD after careful discussion with the patient regarding potential adverse effects, benefits, and other available therapeutic options.[38]

Transoral incisionless fundoplication (TIF) is an entirely endoscopic procedure to reconstruct the gastro-oesophageal valve and help restore an anatomical reflux barrier. In one systematic review and network meta-analysis, short-term likelihood of increased quality of life was greater following TIF than laparoscopic Nissen fundoplication (LNF).[89] LNF was, however, found to have the greatest ability to improve physiologic parameters of GORD. The long-term efficacy of TIF remains to be determined.[90][91]

Candidates for TIF must be carefully selected. In general, a hiatus hernia > 2 cm is considered a contraindication, unless TIF is performed simultaneously with laparoscopic hernia repair.

Emerging endoscopic treatments include anti-reflux mucosectomy and anti-reflux mucosal ablation.[92][93][94][95]

Bariatric surgery

Patients with GORD who are obese may benefit from a bariatric procedure rather than an anti-reflux procedure.[77]

Indications according to BMI, and the best procedure to use, are not established; however, roux-en-Y gastric bypass appears to result in better control of reflux symptoms (up to 70%) compared with other bariatric surgical procedures.[96][97]

Some data suggest that sleeve gastrectomy may worsen or result in de novo GORD.[98]

Management of GORD in pregnancy

Diet and lifestyle modification

Modification of diet and lifestyle is key for the treatment of GORD symptoms in pregnancy.[12][99] Mild GORD symptoms can usually be managed with changes in diet and lifestyle alone. Smaller and frequent meals are recommended. Late-night meals and laying down within 3 hours of meals should be avoided. Consumption of meats, carbonated beverages, fatty foods, and spicy foods should be minimised or avoided to prevent reflux.[12][99]

Management options

Safe and well-established treatment options are available for patients in whom GORD cannot be managed with diet and lifestyle changes alone.[12] Treatment options include antacids, alginates, sucralfate, H2 antagonists, and PPIs.[12] As some women may continue experiencing symptoms in the postnatal period, excretion of the drugs in breast milk and possible effects on the infant should be considered.[99]

Antacids, alginates, and sucralfate are the preferred first-line options. Antacids containing sodium bicarbonate may cause maternal or fetal metabolic alkalosis and fluid overload and should be avoided.[13] Magnesium-containing and calcium-containing antacids can be safely used in lactating mothers as magnesium and calcium salts are poorly absorbed orally; as a result, their blood levels are negligible and only traces may be found in milk, making them a safe alternative.[12] Antacids should be avoided within 2 hours of iron and folic acid supplements, as gastric acid is required for the absorption of these supplements.[13][99]

Combination of an alginate plus an antacid is shown to reduce post-prandial acid reflux.[99][100][101] Owing to limited maternal absorption, alginates are usually considered safe during lactation.[99]

Sucralfate is used to treat gastric ulcers and exerts its mucosal protection through a local effect.[12] Sucralfate has been found to be effective in reducing heartburn and regurgitation symptoms. Based on human and animal studies, it is considered a safe first-line option to treat GORD during pregnancy.[12][13]

If symptoms persist, H2 antagonists are recommended. Famotidine is the preferred H2 antagonist during breastfeeding as least excretion into milk has been reported. Cimetidine has the greatest excretion into milk, but no adverse effects in infants are reported.[12] Nizatidine is not recommended.[12][102]

PPIs are generally considered safe during pregnancy, based on real-world evidence.[12] However, several studies have highlighted risks associated with long-term use of PPIs.[64][65][103][Evidence C]What are the risks associated with long-term use of proton-pump inhibitors (PPIs) compared with no PPIs in people with gastro-oesophageal reflux disorder (GORD)?[64] Thus, the use of PPIs should be restricted to women with intractable symptoms or complicated reflux disease.[13][102] Omeprazole should be avoided in both pregnancy and lactation.[99]

Additional testing (upper GI endoscopy, oesophageal manometry, and reflux testing) may be necessary in case of persistent GORD symptoms.

Potential risks of long-term proton-pump inhibitor (PPI) therapy

Several studies have highlighted risks associated with long-term use of PPIs; therefore, attempts to stop or reduce the dose to the minimum necessary to maintain symptomatic control should always be pursued.[64][65][103][Evidence C]What are the risks associated with long-term use of proton-pump inhibitors (PPIs) compared with no PPIs in people with gastro-oesophageal reflux disorder (GORD)?[64]

One observational study using a Dutch primary care database (n=148,926) found that PPIs were inappropriately continued in 32% of patients following a short-course therapy for dyspepsia and in 11% of patients following ulcer prophylaxis.[104]

Theoretical clinical sequelae of chronic acid inhibition are not considered a barrier to long-term therapy.[3][64][105] There is no defined role for screening for possible adverse effects or for avoidance of acid suppression because of possible adverse effects.[3][106]

PPIs should only be prescribed for appropriate indications and should be limited to the warranted therapeutic duration of therapy. Based on current data, the overall benefits of PPI treatment outweigh the potential risks in most patients.

The American Gastroenterology Association recommends:[105]

All patients taking a PPI should have a regular review of the ongoing indications for use, and those without a definitive indication for chronic PPI use should be considered for a trial of de-prescribing.
PPI de-prescribing should not be considered in patients with complicated gastro-oesophageal reflux disease (e.g., history of severe erosive oesophagitis, oesophageal ulcer, or peptic stricture), known Barrett’s oesophagus, eosinophilic oesophagitis, idiopathic pulmonary fibrosis or in patients at high risk for upper gastrointestinal bleeding. When de-prescribing, dose tapering or abrupt discontinuation can be considered.
Patients with an indication for twice-daily PPI dosing should be considered for a step down to once-daily dosing.
Patients discontinuing long-term PPI therapy should be advised that they may develop transient upper gastrointestinal symptoms due to rebound acid hypersecretion. Patients should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.

A holistic approach for managing symptoms on an individual level has been suggested. PPI prescribing and deprescribing can be supported with lifestyle counselling, education programs, and symptom relief while the patient returns to self-care.[107]

Retrospective analyses suggest an association between PPI use and osteoporosis, bone fracture, pneumonia, dementia, hypomagnesaemia, Clostridium difficile-associated diarrhoea, chronic kidney disease, and stroke.[108][109][110][111][112][113] These studies are unable to establish a causal relationship.

Results from one large population-based cohort study suggest that PPIs are associated with a 45% increased risk of gastric cancer, compared with H2 antagonists, and the risk was proportional to the cumulative duration of therapy and dose.[114]

Prospective study findings

In one large, adequately powered, prospective randomised trial to evaluate long-term PPI safety concerns in patients with stable cardiovascular disease (n=17,958), no significant difference in adverse effects was reported between pantoprazole and placebo at 3 years, aside from a possible increase in non- Clostridium difficile enteric infections.[115] Data from this randomised trial suggest that associations reported in observational studies may relate to residual confounding or biases. Smaller randomised controlled trials of patients with GORD indicate that long-term treatment with a PPI is safe and effective.[116][117][118][119]

Prospective cohort studies (n=204,689) have reported an increased risk of type 2 diabetes in people who used PPIs for >2 years, compared with non-users (hazard ratio 1.26, 95% confidence interval [CI] 1.18 to 1.35).[120]

One population-based nested case-control study (n=777,420) found that using PPIs on a regular basis for longer durations was associated with a higher risk of diabetes.[121] According to the study, patients who used PPIs for between 8 weeks and 6 months, 6 months and 2 years, and >2 years had 19% (95% CI 15% to 24%), 43% (95% CI 38% to 49%), and 56% (95% CI 49% to 64%) higher odds of diabetes, respectively, compared with those who used PPIs for <8 weeks.

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