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MikkoKiviniemi

Gastro-Oesophageal Reflux Disease

Essentials

  • The main symptoms of gastro-oesophageal reflux disease (GORD, also GERD) are heartburn and regurgitation.
  • If the patient is under 50-55 years of age and does not have alarming symptoms the diagnosis of the disease is based on symptoms.
  • The most effective drug treatment for reflux symptoms and reflux oesophagitis is a proton pump inhibitor (PPI) taken once daily, 30-60 minutes before breakfast.
  • All patients should also be given instructions for non-pharmacological treatment.
  • As many as 30% of the patients have an unsatisfactory response to conventional drug treatment (refractory gastro-oesophageal reflux disease).
  • An endoscopic examination of the upper gastrointestinal tract should be carried out in patients over 50 to 55 years and those in whom PPI therapy started on clinical grounds proves ineffective or who have alarming signs and/or symptoms:
    • dysphagia or pain on swallowing
    • vomiting
    • weight loss
    • anaemia
    • severe symptoms resistant to conventional treatment.

Epidemiology

  • GORD is often a chronic condition.
  • In Western countries, 10-20% of the population have symptoms of GORD.
  • The incidence is 5 cases per 1 000 person years.

Aetiology

  • Transient lower oesophageal sphincter relaxation (TLOSR) not associated to swallowing is the principal aetiological factor and causes 90% of cases.
  • The majority of patients with severe GORD also have hiatus hernia.
  • Oesophageal injury is caused by gastric hydrochloric acid and pepsin; and to a lesser extent by bile acids.
  • Saliva neutralises the refluxate and, reduced salivary secretion increases the risk of GORD.
  • Smoking reduces the secretion of saliva and acts as a predisposing factor to GORD.
  • Other predisposing factors include pregnancy, scleroderma, Sjögren's syndrome and diabetic gastroparesis.

Clinical picture

  • Heartburn, a burning sensation behind the sternum, is the main symptom of GORD.
    • Heartburn is a burning pain or an unpleasant sensation that starts at the epigastrium or the lower part of the sternum and radiates to the neck (the symptom should be described to the patient).
    • Heartburn is typically experienced after a meal or when lying down. Heartburn is particularly associated with large meals, foods high in fat, chocolate, coffee, strong alcoholic drinks (spirits) and acidic fruit juices. Bending over, lifting and tight clothing also aggravate heartburn.
    • Of patients with GORD, 75% suffer from heartburn.
  • Another main symptom is regurgitation, which means the flow of stomach contents back up into the throat without being associated with nausea or vomiting.
  • Other symptoms include a feeling of a lump in the throat (globus sensation), difficulty swallowing (dysphagia) Dysphagia and Globus Sensation (Globus Pharyngeus) and intermittent reflux-associated hypersalivation.
  • GORD is the main non-cardiac cause of chest pain.
  • Extraoesophageal manifestations may include laryngitis, asthma, chronic cough, and erosion of dental enamel.
  • The clinical diagnostic criteria for GORD are the occurrence of reflux symptoms at least twice a week and impairment of the quality of life because of these symptoms (eating, sleeping, physical straining).
  • In 70% of reflux patients (in > 90% of those who have received PPIs), oesophagoscopy shows normal findings. If PPIs have not been used, the disease is called nonerosive or endoscopy-negative reflux disease (NERD).
  • If oesophagoscopy reveals mucosal erosions in the distal oesophagus, the disease is called erosive reflux disease (ERD), which is classified into severity grades B to D according to the Los Angeles Classification. Mild erosive oesophagitis (Los Angeles A) is not a definite diagnostic criterion for GORD because it is seen in 5-7.5% of people without the disease.
  • The complications of GORD include oesophageal stricture and ulcer as well as Barrett's oesophagus.
  • An epidemiological connection between GORD and the extraoesophageal symptoms and findings (cough, laryngitis, asthma and erosion of dental enamel) has been found. GORD is, however, just one possible aetiological factor of these symptoms.

Diagnosis

  • When a patient presents for the first time with symptoms of GORD (heartburn, regurgitation) the duration and frequency (times/week) of the symptoms should be determined. The patient should also be asked whether the symptoms occur only during the day or also at night time. If alarming symptoms are not present and the patient is under 55 years of age the diagnosis can be established without endoscopy.
  • A patient with alarming symptoms (dysphagia Dysphagia and Globus Sensation (Globus Pharyngeus), pain on swallowing, vomiting, haematemesis, weight loss, anaemia) should be referred for endoscopy without delay.
  • If the patient has dyspeptic symptoms Dyspepsia, in addition to the symptoms of GORD, an endoscopic examination should be carried out for the purpose of differential diagnosis, to exclude peptic ulcer etc.
  • Other factors that speak for an early endoscopy also include age > 50-55 years, use of a non-steroidal anti-inflammatory analgesic drug or aspirin, smoking, heavy consumption of alcohol as well as upper GI tract cancers diagnosed in close relatives.
  • Endoscopic assessment of the oesophagus can be used to classify the type of GORD (erosive or non-erosive), to grade the severity of erosive GORD (Los Angeles Classification, table T1) and to identify possible complications, such as Barrett's oesophagus (a histological finding of intestinal metaplasia with immature cells), oesophageal ulcer or stricture.
  • An endoscopic finding of histologically verified oesophagitis has little diagnostic value, but biopsies are required for the differential diagnosis of GORD as well as of eosinophilic and infectious oesophagitis.
  • Oesophageal function studies are used in the differential diagnostics of GORD and in assessment of the outcome of surgical treatment.
    • Oesophageal impedance (+ pH) monitoring can be used in specialized care to study both liquid and gas reflux. Precision manometry can be used to diagnose motor disorders of the oesophagus more reliably than in the past.
    • Prolonged (24 hour) oesophageal pH monitoring and manometry are conventional investigations of oesophageal function used in specialized care.
  • In connection with the function studies, it is important to determine the temporal correlation between symptoms and findings (symptom index [SI], symptom association probability [SAP]).

Proton pump inhibitor (PPI) test

  • In the PPI test the patient takes a proton pump inhibitor at double dosage (normal therapeutic dose morning and evening) for one week, i.e. omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily, pantoprazole 40 mg twice daily, rabeprazole 20 mg twice daily, esomeprazole 20 mg twice daily.
  • The test result is positive if symptoms diminish by at least 75%.
  • The test is used when the cause of non-cardiac chest pain is suspected to be GORD.
  • The test has high sensitivity but low specificity. The PPI test also often gives positive results in people without GORD (the course of PPI decreasing symptoms); therefore, a positive test result does not always imply GORD.

Endoscopic grading of GORD

  • The selection and duration of drug therapy depend on the severity of endoscopic oesophagitis, which can be graded with the aid of the Los Angeles Classification system (see table T1).
  • Most patients with GORD have normal findings on oesophageal endoscopy, i.e. they have non-erosive reflux disease.

Grading of oesophagitis (Los Angeles Classification System)

Grade1) Endoscopic finding 2)
AOne or more mucosal breaks no longer than 5 mm that do not extend between the tops of two mucosal folds
BOne or more mucosal breaks more than 5 mm long that do not extend between the tops of two mucosal folds
COne or more mucosal breaks that are continuous between the tops of two or more longitudinal mucosal folds but which involve less than 75% of the circumference
DOne or more mucosal breaks that involve at least 75% of the oesophageal circumference
  1. Grades C and D = severe oesophagitis. Complications of oesophagitis, such as strictures, ulcers and Barrett's metaplasia, are graded separately.
  2. A mucosal break is a reddish or fibrin-covered area clearly demarcated from the adjacent normal appearing mucosa.
Treatment

Treatment goals (uncomplicated GORD)

  • Relief of symptoms
  • Treatment of erosive oesophagitis
  • Prevention of recurrent oesophagitis

Lifestyle modifications and antacid or alginate therapy

  • Regardless of the severity of GORD symptoms, all patients should be instructed to use non-pharmacological treatment.
    • Weight reduction if BMI ≥ 25.0
      • A patient of normal body weight (BMI < 25.0) may also benefit from weight reduction if the onset of GORD symptoms coincided with weight gain.
    • Raising the head of the bed (nocturnal symptoms)
    • Avoidance of tight clothes around the waist
    • Avoidance of evening meals (nocturnal symptoms)
    • Frequent small meals (postprandial symptoms)
    • Avoidance of foods that provoke symptoms: citrus fruit, strong alcoholic drinks, tomatoes, onions, strong spices, fatty or fried food, carbohydrates, foods containing caffeine or theobromine, such as coffee, cocoa, chocolate
    • Smoking cessation
    • Reducing or stopping the consumption of alcohol
    • Avoidance of certain drugs (nitrates, calcium channel blockers, anticholinergics, theophylline preparations)
    • Moderate exercise may alleviate the symptoms.
  • Antacids and alginates are suitable as monotherapy for mild symptoms of short duration but should also be used as adjuvant treatment combined with PPIs. Their effect starts in 5 minutes but only lasts 30-60 minutes.

Pharmacotherapy with proton pump inhibitors Proton Pump Inhibitors for Prolonged Non-Specific Cough in Gastroesophageal Reflux Disease, Proton-Pump Inhibitors for Non-Erosive Reflux Disease, Continuous Vs Intermittent Proton Pump Inhibitors for Gastroesophageal Reflux Disease

  • The principles of pharmacotherapy are the same whether the patient has not undergone endoscopy or has endoscopy-negative GORD or endoscopy-positive mild GORD.
  • A proton pump inhibitor (PPI) is the drug of choice.
  • The use of H2-receptor antagonists has decreased and only few preparations are available.
  • The FDA (US Food and Drug Administration) has defined the minimum doses of different PPIs that alleviate the symptoms of GORD: esomeprazole 20 mg, omeprazole 20 mg, lansoprazole 15 mg, pantoprazole 40 mg and rabeprazole 20 mg once daily. PPIs are taken 30-60 minutes before breakfast.
  • The dose of a PPI and the duration of the treatment are determined according to the severity of reflux oesophagitis (Los Angeles Classification, Table T1).
  • The response to a PPI dose varies from patient to patient. This may be due to the inherited activity of the PPI-metabolising cytochrome P450 enzyme (CYP2C19), the patient's Helicobacter status or the relationship of the dosing times to food intake.
  • The use of PPIs during pregnancy is considered safe.

Mild oesophagitis (Grade A or B)

High-grade oesophagitis (Grade C or D)

  • PPI therapy
  • If the symptoms do not improve with once daily dosing, twice daily dosing (a PPI half an hour before breakfast and supper) should be tried.
  • The healing of severe, i.e. grade C to D, reflux oesophagitis should be confirmed endoscopically.
  • Patients with severe erosive oesophagitis will need permanent maintenance therapy with a PPI (the dose is usually that which rendered the patient asymptomatic at the initial stage) or surgical management (fundoplication).

Prevention of recurrence of GORD

  • Oesophagitis or symptoms recur in 60-80% of the patients within one year after medication is withdrawn.
  • The need for prophylactic treatment should be assessed individually for each patient. Most patients manage without prophylactic medication and only use medication when needed (”on demand” or as short courses).
  • Non-pharmacological treatment may be used for the prevention of recurrence.
  • No oesophagitis on endoscopy: A PPI once daily or when required
    • The lowest effective dose should be chosen.
  • Mild reflux disease: A PPI once a day, either a full or half therapeutic dose (omeprazole 10-20 mg once daily; lansoprazole 15-30 mg once daily; pantoprazole 40 mg once daily; rabeprazole 10-20 mg once daily; esomeprazole 20 mg once daily)
  • Severe oesophagitis: prophylactic treatment in every case (see above).

Unsatisfactory treatment response, and treatment-resistant, or refractory, GORD

  • Treatment response is unsatisfactory if the symptoms have not been reduced by more than a half after 3 months of treatment with the normal (by some definitions, double) dose of PPI.
  • Firstly, adherence to treatment and correct dosing time (30-60 minutes before breakfast) should be checked.
  • In 30% of patients, correctly implemented PPI treatment does not produce an adequate response within 3 months. In this case, the patient should be referred for endoscopy if it has not been performed earlier.
  • A double dose of PPI is usually prescribed in treatment-resistant cases, i.e. a normal therapeutic dose each morning and evening (before breakfast and supper). An alginate preparation may be combined into the treatment.
  • Replacement of one PPI by another may improve the treatment result.
  • Reasons for failure of PPI treatment and states to be considered in differential diagnosis:
    • Nonadherence to treatment
    • Wrong PPI dose or wrong timing of medication
    • Fast PPI metabolism
    • Nonacid reflux
    • Functional heartburn
    • Increased oesophageal sensitivity
    • Oesophageal motility disorder
    • Eosinophilic oesophagitis
    • Rumination
    • Aerophagia
    • Functional dyspepsia
  • If the endoscopy findings are normal and correctly implemented PPI therapy is ineffective, the differential diagnosis should be reconsidered and the patient referred for oesophageal function studies, as necessary.
  • Patients with functional heartburn, or irritable or acid-sensitive oesophagus often have poor response to PPI. They may benefit from SSRI medication (citalopram or fluoxetine for 6 weeks or longer).
  • If the patient's main symptom during adequate PPI treatment is regurgitation, baclofen medication may be beneficial (5-10 mg 3 times daily before meals or 5-20 mg in the evening). However, baclofen often causes neurological (vertigo, tiredness, drowsiness) and gastrointestinal (nausea, diarrhoea, flatulence) adverse effects.

Treatment of GORD during pregnancy and breast-feeding

  • During pregnancy, the treatment of choice is non-pharmacological treatment, i.e. lifestyle changes.
  • Sleeping on the left side and moderate exercise may alleviate GORD symptoms.
  • Antacids and alginates are safe to use during pregnancy.
  • Sucralfate can be used during pregnancy and lactation.
  • PPIs can be used if a sufficient treatment response cannot be achieved by other drugs. PPIs have not been found to be associated with an increased risk of malformations in humans. There is most experience of the use of omeprazole but the risks of other PPIs are also considered minor.
  • PPIs are excreted in breast milk to a small extent, only, and their use during breast-feeding is considered safe.

Surgical management

  • The results of surgical treatment are best in cases where there is objective evidence of GORD and a response has been obtained with PPI therapy.
  • Indications
    • Severe erosive oesophagitis (Grade C-D) not rendered asymptomatic with continuous medication, or the patient is reluctant to use continuous medication.
    • Complicated erosive oesophagitis (e.g. bleeding, ulcer, stricture)
    • Regurgitation as the dominant symptom
    • Adverse effects of medication

Long-term treatment

  • If symptoms recur within less than 3 months after conventional 8-week PPI treatment, long-term medication should be started. If so, gastroscopy should be performed if not done earlier.
  • The lowest PPI dose required to keep the patient free of symptoms should be used. Occasional symptoms may be treated with on-demand therapy using a PPI.
  • Long-term PPI treatment is indicated if the patient has constant or recurrent symptoms of erosive, nonerosive or complicated GORD (ulcer, stricture, Barrett's oesophagus).
  • Long-term use of PPIs may be associated with low stomach acid, hypergastrinaemia, parietal or enterochromaffin cell hyperplasia or the development of fundic gland polyps of carcinoid tumours. If a Helicobacter carrier requires long-term PPI therapy, eradication therapy is recommended.
  • Long-term PPI therapy increases the risk of enteric infections.
  • Long-term use of PPIs has been observed to be associated with malabsorption (calcium, magnesium, vitamin B12, iron) and infections (pneumonia, intestinal infections). However, the absolute risk of complications is low, and it is highest in patients who are elderly or undernourished or who have multiple diseases.
  • PPIs have been reported to reduce the effectiveness of antithrombotic medication in several observational studies, but clinically significant interactions have not been detected in randomized controlled trials. If the patient has GORD that requires pharmacotherapy, PPIs can be used together with antithrombotic medication. PPIs also reduce the risk of upper gastrointestinal bleeding associated with antithrombotic medication.
  • Surgery (Nissen fundoplication) is required in less than 10% of patients with reflux oesophagitis.
  • The long-term results of laparoscopic fundoplication surgery are good: after 10 years, 70% of the patients operated on have a good surgical outcome and a good quality of life.

Follow-up

  • Mild oesophagitis need not be followed up endoscopically if the symptoms are relieved.
  • It is recommended that the healing of severe oesophagitis is confirmed by endoscopy 2 months after starting drug therapy.
  • If no oesophagitis is detected in endoscopy, GORD should be treated in the same way as reflux oesophagitis. Monitoring or follow-up is unnecessary if the symptoms are relieved.

Complications

  • Reflux oesophagitis is usually a mild disease without serious complications.
  • Some patients with GORD will develop Barrett's oesophagus where the squamous epithelium of the distal oesophagus is replaced by mucous membrane that contains immature intestinal metaplasia (specialised columnar epithelium).
    • Barrett's oesophagus is associated with an increased risk of adenocarcinoma of the oesophagus (annual risk ≤ 0.5%).
    • The risk is highest in smoking, obese men over 60 who have had symptoms of GORD for a long time.
    • The physician who performed the endoscopy must take a stand on whether endoscopic follow-up is necessary in a patient whose Barrett lesion does not contain dysplasia.
    • Follow-up is essential if slight dysplasia is found in Barrett's oesophagus. Any patient with severe dysplasia should be referred to a centre with endoscopic treatment available.
  • Chronic, ulcerating oesophagitis may cause strictures and dysphagia. Oesophagitis causes about 7% of all gastrointestinal bleeds. Oesophageal bleeding nearly always consists of slow oozing that results in anaemia.

    References

    • Hoogendoorn RJ, Groeneveld L, Kwee JA. Patient satisfaction with switching to esomeprazole from existing proton pump inhibitor therapy for gastro-oesophageal reflux disease: an observational, multicentre study. Clin Drug Investig 2009;29(12):803-10. [PubMed]
    • Scarpellini E, Ang D, Pauwels A et al. Management of refractory typical GERD symptoms. Nat Rev Gastroenterol Hepatol 2016;13(5):281-94. [PubMed]
    • Reimer C. Safety of long-term PPI therapy. Best Pract Res Clin Gastroenterol 2013;27(3):443-54. [PubMed]
    • Berger PB. Should proton pump inhibitors be withheld from patients taking clopidogrel? The issue that has been giving me heartburn! Circ Cardiovasc Qual Outcomes 2015;8(1):6-7. [PubMed]
    • Melloni C, Washam JB, Jones WS et al. Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes 2015;8(1):47-55. [PubMed]
    • Gerson LB. Treatment of gastroesophageal reflux disease during pregnancy. Gastroenterol Hepatol (N Y) 2012;8(11):763-4. [PubMed]
    • Gyawali CP, Kahrilas PJ, Savarino E et al. Modern diagnosis of GERD: the Lyon Consensus. Gut 2018;67(7):1351-1362. [PubMed]
    • van der Woude CJ, Metselaar HJ, Danese S. Management of gastrointestinal and liver diseases during pregnancy. Gut 2014;63(6):1014-23. [PubMed]
    • Fisichella PM, Patti MG. GERD procedures: when and what? J Gastrointest Surg 2014;18(11):2047-53. [PubMed]
    • Bytzer P, Jones R, Vakil N et al. Limited ability of the proton-pump inhibitor test to identify patients with gastroesophageal reflux disease. Clin Gastroenterol Hepatol 2012;10(12):1360-6. [PubMed]

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