Reflux Hypersensitivity

Reflux hypersensitivity is a functional oesophageal disorder with typical reflux symptoms (retrosternal burning, chest pain, regurgitation). Endoscopy and acid exposure time on reflux monitoring are normal, with no major motility disorder and no eosinophilic oesophagitis. Symptoms show a positive association with reflux events (acid or weakly acidic reflux) on pH or pH-impedance monitoring.

• The oesophagus is hypersensitive to physiological reflux events. The mechanisms are peripheral sensitisation (mucosal barrier dysfunction, widened intercellular spaces, inflammation, and sensory nerve activation) and central sensitisation (altered processing of pain in the spinal cord and brain). Psychological factors (anxiety, hypervigilance, and stress) contribute.
• It is a distinct condition from non-erosive reflux disease (where acid exposure is abnormal) and functional heartburn (where there is no symptom reflux association). The three conditions sit on a spectrum, and overlap is common.
• Prevalence: about 10 to 20% of patients with persistent reflux symptoms and normal endoscopy, and up to 20 to 30% of those who are refractory to proton pump inhibitors who undergo reflux testing off therapy. Women and younger patients are affected more often.
• Risk factors: anxiety and depression, other functional disorders (irritable bowel syndrome, functional dyspepsia, globus), previous gastro oesophageal reflux disease, hiatus hernia, a low body mass index, and psychological stress.
• The condition is chronic and fluctuating, and does not lead to Barrett oesophagus or oesophageal adenocarcinoma.

• Heartburn, retrosternal chest pain, regurgitation, and sometimes cough or throat symptoms (globus, hoarseness), occurring at least twice weekly for the last 3 months, with onset at least 6 months before diagnosis. Symptoms can be triggered by meals, certain foods (fatty, spicy, acidic), alcohol, and stress, and are partially responsive or unresponsive to proton pump inhibitors.
• Symptoms often occur without objective evidence of acid damage, and patients may be highly aware of reflux events and concerned about symptoms.
• Examination is normal.
• Differential diagnosis: non-erosive reflux disease, erosive reflux disease, functional heartburn, eosinophilic oesophagitis, achalasia, oesophageal spasm, rumination syndrome, pill oesophagitis, peptic ulcer disease, gastroparesis, biliary disease, functional dyspepsia, and angina.
• Red flags: dysphagia, odynophagia, weight loss, gastrointestinal bleeding, anaemia, persistent vomiting, age over 55 years with new symptoms, a family history of upper gastrointestinal cancer, chest pain on exertion, and a palpable mass.
• Complications: reduced quality of life, sleep disturbance, long term unnecessary proton pump inhibitor use, repeated investigation, and surgery that fails to relieve symptoms.

• Diagnosis requires objective testing off acid suppression, because symptoms alone cannot separate the conditions.
• Upper endoscopy: normal mucosa (no erosive oesophagitis of grade B or above, no Barrett oesophagus, no stricture), with biopsies to exclude eosinophilic oesophagitis.
• Ambulatory 24 hour pH-impedance monitoring off proton pump inhibitors (stopped for 7 days) or a wireless pH capsule for 96 hours:
  • Acid exposure time below 4%.
  • A normal number of reflux episodes (below 40 in 24 hours).
  • A positive symptom association, for acid or non-acid reflux:
    • A symptom index of 50% or more (the percentage of symptom events preceded by a reflux event within 2 minutes).
    • A symptom association probability of 95% or more (a statistical measure that symptoms and reflux are linked).
• High resolution oesophageal manometry to exclude achalasia, absent contractility and other major motility disorders.
• Optional: barium swallow, gastric emptying study, and a short course of high dose acid suppression before testing (a proton pump inhibitor twice daily for 8 weeks) if the clinical diagnosis is of reflux disease.
• Screen for anxiety, depression and somatic symptom disorder.

• Explain the diagnosis, the concept of visceral hypersensitivity, and the favourable outlook, and set realistic goals of symptom reduction rather than complete elimination.
• Lifestyle measures:
  • Avoid trigger foods (fatty, spicy, citrus, chocolate, coffee, alcohol, carbonated drinks).
  • Eat smaller more frequent meals, and avoid meals within 3 hours of bedtime.
  • Raise the head of the bed by 10 to 15 cm if night symptoms.
  • Lose weight if overweight (a loss of 5 to 10% improves symptoms), stop smoking, and wear loose clothing.
• Acid suppression (for those with a symptom association with acid reflux or when symptoms respond):
  • Omeprazole 20 mg orally once daily (or esomeprazole 20 to 40 mg, lansoprazole 30 mg, pantoprazole 40 mg, or rabeprazole 20 mg) taken 30 to 60 minutes before breakfast, for 8 weeks.
  • Increase to twice daily only for those who show a partial response, for another 4 to 8 weeks. If there is no benefit, stop it, and move to neuromodulators.
  • Famotidine 20 mg orally 12 hourly or 40 mg at night as a add on for night symptoms, with tolerance developing in 2 to 4 weeks.
  • Alginate (sodium alginate and potassium bicarbonate 10 to 20 mL after meals and at bedtime) for weakly acidic reflux and breakthrough symptoms.
  • Potassium competitive acid blockers (vonoprazan 10 to 20 mg once daily) where available.
• Neuromodulators (central to treatment of hypersensitivity):
  • Amitriptyline 10 mg orally at night, increased by 10 mg every 1 to 2 weeks to 25 to 50 mg, or imipramine 10 to 25 mg at night, or nortriptyline 10 to 25 mg at night, for 8 to 12 weeks.
  • Citalopram 10 to 20 mg orally once daily, or sertraline 25 to 100 mg once daily, especially with comorbid anxiety or depression. Venlafaxine extended release 37.5 to 75 mg once daily, or trazodone 50 to 100 mg at night, are alternatives.
  • Monitor for adverse effects (dry mouth, constipation, drowsiness, QT prolongation), and review after 8 to 12 weeks.
• Baclofen 5 mg orally 3 times daily before meals, increased to 10 mg 3 times daily, reduces transient lower oesophageal sphincter relaxations and weakly acidic reflux, in patients with regurgitation and belching. Adverse effects are drowsiness and dizziness (reduce the dose in renal impairment, and withdraw gradually).
• Psychological therapies: cognitive behavioural therapy, gut directed hypnotherapy, diaphragmatic breathing, and relaxation, which improve symptoms in about 50 to 60% of patients.
• Avoid antireflux surgery (it has a poor result in hypersensitivity without abnormal acid exposure), and repeated or escalating proton pump inhibitor doses without benefit.
• Special groups:
  • Pregnancy: alginate, calcium carbonate antacids, and, when needed, omeprazole 20 mg daily or famotidine 20 mg daily. Avoid baclofen and neuromodulators unless essential.
  • Elderly: use lower doses of neuromodulators (amitriptyline 10 mg), avoid tricyclics with falls or cognitive impairment, and review the need for long term proton pump inhibitor treatment (risk of fracture, hypomagnesaemia, infection, and vitamin B12 deficiency).
  • Children and adolescents: exclude eosinophilic oesophagitis, give reassurance, use lifestyle measures, and avoid long term medication.
  • Renal impairment: reduce baclofen, and monitor magnesium with long term proton pump inhibitors.
  • Cardiac disease: exclude angina, and review QT-prolonging combinations.
• Follow up: review at 8 weeks after any treatment change, and every 3 to 6 months afterwards. Taper acid suppression to the lowest effective dose or stop it. Refer to a gastroenterologist for refractory symptoms, uncertain diagnosis, or new alarm features, and to a psychologist for significant anxiety or somatic symptom disorder.