gastro-oesophageal reflux

see also:

• Dyspepsia
• oesophagitis in adults
• eosinophilic oesophagitis (EoE)
• oesophageal cancer
• gastroenterology
• the adult patient with chest pain in the ED

• often abbreviated as GOR, GORD or GERD (gastro-esophageal reflux disease)
• one of the most common causes of retrosternal chest pain often confused with cardiac pain, hence its common name - heartburn
• heartburn appears to be a cortical perception of a variety of intra-oesophageal events, of which acid reflux is only one
• acid-induced esophageal pain is likely to be mediated by vanilloid receptor 1 (VR1) and by anion-sensing ion channels (ASICs)¹⁾
• 10-20% of adults in Western countries have some degree of GOR symptoms each month
• the prevalence of GOR in which the cardinal symptom is heartburn appears to increase with advancing age:
  • 20% of patients older than age 65 years complain of heartburn symptoms once a week and 59% at least once a month
• evidence of reflux is usually demonstrated via either:
  • gastroscopic evidence of oesophagitis
  • oesophageal pH monitoring demonstrating fall in pH below 4
  • the PPI Test - presumptive evidence via symptom response to high dose PPI 7 day test:
    • eg. omeprazole 40mg bd for 7 days reduced symptoms in over 80% of NERD patients
• some patients experience heartburn in the absence of abnormal acid exposure or oesophagitis on gastroscopy (non-erosive reflux disease “NERD”)
  • this group is actually the most common phenotypic presentation of GOR accounting for 50-70% of cases of GOR and tends to be younger, female, and lack hiatal hernia, and fortunately, only 10-15% go onto to erosive oesophagitis (usually mild) with very few if any developing Barrett's or adenocarcinoma.
  • ~60% of these patients will respond to 4 week course of proton pump inhibitors (PPIs) - eg. omeprazole 20mg/d
  • non-responders to PPI's should be considered for Rx with visceral pain modulators such as low dose SSRI/SNRI antidepressants
  • 40% of these “NERD” patients appear to develop pain to minimal change of oesophageal pH and are thus “hypersensitive”²⁾
  • the other 60% of these patients have pain without any change in oesophageal pH and are regarded as “functional” as no pathology is found, and they usually fail to respond to proton pump inhibitors (PPIs) because acid is not the cause of their symptoms, but perhaps is more related to dysautonomia syndromes as autonomic nerves play a central role in the modulation of visceral noxious stimuli.
    • electron microscopy research suggests that the presence of dilated inter-epithelial spaces seen in patients with NERD results in an increase in paracellular permeability, allowing acid and other reflux components to reach nerve endings that are located within the esophageal mucosa, leading to a heartburn sensation.
    • other factors may increase the sensation of pain including anxiety, stress hormones, progestogens, and impaired quality of sleep.
• some patients with severe oesophagitis and complications such as Barrett's oesophagus have absent or little heartburn
• interestingly H. pylori infection may be associated with reduced incidence of GOR - perhaps via reduced gastric acid secretion.
• there is a relationship with asthma - perhaps minute amounts of gastric reflux aspirating into the pulmonary system causes wheezing, perhaps the asthma itself or its drug medications relax the LES, or perhaps there is a role for the associated viral URTI in relaxing the LES
• although proton pump inhibitors (PPIs) can give symptom control of erosive GOR even after 4 weeks of standard dose Rx, if Rx is discontinued, GOR will relapse in 75% of patients within 6 months ³⁾

• deep retrosternal chest pain is the prime symptom but there may be little if any pain and still produce a chronic oesophagitis
  • this may range from a knot-like deep chest discomfort, to deep central burning pain to a very severe deep retrosternal pain which may radiate to the jaw or shoulder in a similar manner as acute myocardial infarction (AMI/STEMI/NSTEMI)
  • pain is usually most prominent after a big meal or at night when supine and is not otherwise related to position, movement, exertion or respiration.
  • contrary to popular thought it may not respond to oral antacids, PPI's (as these may decrease further burns but do not take the pain away from an existing acid burn episode or the associated muscle spasm or pain associated with inflammatory mediators) or oral local anaesthetics (as these are deactivated in acid environments), but may be partly relieved by nitrates if there is marked oesophageal spasm (although nitrates by relaxing the lower oesophageal sphincter (LES) would predispose to further reflux and injury).
  • characteristics that may differentiate oesophageal pain from cardiac angina include the provocation of pain with meals and certain postures, periods of prolonged remission, nocturnal symptoms, delayed relief from nitroglycerine (10 minutes or longer), and the association with specific oesophageal symptoms.
• possible associated features:
  • burping is common
  • nausea may occur
  • sensation of reflux of stomach contents to back of throat - actual regurgitation may occur on bending over or in supine position
  • some may develop sore throat, hoarse voice or wheezing depending on extent of proximal reflux

• Nature - pathophysiology of GERD
• the two prime aetiologic mechanisms required to cause GOR are:
  • failure of the LES to prevent reflux of gastric contents into the oesophagus:
    • prolonged relaxation of the LES
      • the LES is tonically closed at rest, maintaining an average pressure of about 20 mmHg, and serves to prevent GOR
      • to allow passage of a bolus, LES pressure falls within 1.5 to 2.5 seconds of a swallow and remains low for 6 to 8 seconds as the peristaltic contraction transverses the oesophageal body.
      • the LES is composed of two muscles:
        • circumferential smooth muscle forming a partial ring
          • has significant spontaneous tone and relaxes via nitric oxide mechanisms and via calcium channel blockers
          • intrinsic tone is mediated via L-type calcium channel and is unaffected by anticholinergics
        • longitudinal gastric sling muscle completes the ring
          • has little spontaneous tone but contracts via vagal cholinergic stimulation via non-L-type calcium channels (this is turned off during swallowing and with anticholinergics but not by L-type calcium channel blockers)
    • hiatus hernia
      • markedly reduces the effectiveness of the LES
  • noxious irritants in the refluxing fluid:
    • gastric acid is the prime noxious agent but its actions are increased by the presence of gastric pepsin and bile
    • capsaicin, an active ingredient in chili peppers, is a key activator of VR1 pain receptor which in turn can induce a neurogenic inflammatory process⁴⁾
• other factors:
  • reduced salivary secretions which normally help to clear reflux from the oesophagus
  • oesophageal mucosal defence mechanisms
    • is mucosal dysfunction that produces abnormal tissue resistance an explanation for some or all of the variances seen?
  • genetic factors
  • functional factors perhaps associated with dysautonomia syndromes may explain those with NERD
    • is visceral hypersensitivity peripheral and/or central, hyperalgesia or allodynia (a painful response to normally nonpainful stimuli)
    • do sensations such as heartburn arise from abnormal contractions such as sustained esophageal contractions of circular or longitudinal muscle, and/or distention
• self-perpetuating factors:
  • inflammatory mediators released from inflammation due to reflux burn injury may cause:
    • relaxation of LES via:
      • PGE2 (and also blocks PGF2a mediated contraction of LES)
      • increased mucosal IL-6 increases hydrogen peroxide production within the muscle which appears to be the main factor increasing PAF and PGE2, both of which can reduce ACh release and LES muscle tone.
      • increased NO levels
    • shortening of the oesophagus and thus perhaps a factor in causing hiatus hernia:
      • via inflammatory mediators and NO

• high BMI
• hiatus hernia
• advancing age
• genetic factors
• pregnancy

• calcium channel blockers
• nitrates including GTN
• anti-muscarinic anticholinergic agents
• progestogens (relax smooth muscle hence often worse in pregnancy)
• non-steroidal anti-inflammatory drugs (NSAIDs) may cause direct irritation as with mechanism of peptic ulcer disease (PUD)
• caffeine
• ethanol (alcohol and alcohol withdrawal)
• barbecued meat and fried foods
• citrus foods
• peppermint
• capsicum:
  • often effect is delayed by up to 12 hours or more following ingestion
  • capsaicin, an active ingredient in chili peppers, is a key activator of VR1 pain receptors in the oesophagus
• spices
• hot drinks - perhaps via activation of VR1 pain receptor if temp > 48degC but lower temperatures in presence of reflux - habitual hot black tea is associated with oesophageal cancer.
• any food can exacerbate GOR in the presence of reflux by stimulating gastric acid secretion and also by causing gastric distension