Heartburn

This is one symptom of indigestion or ‘functional dyspepsia’. It is a burning sensation in the middle of the chest, usually after eating and worsened when lying down or stooping. It is often associated with

• increased visceral activity such as irritable bowel syndrome (IBS)
• ‘diaphragmatic spasm’ linked to stress, with hyperventilation (shallow breathing) and palpitations
• abdominal congestion such as pregnancy, obesity, or bloating.

Stress in heartburn is also associated with increased sensitivity of the lower oesophageal mucosa (1).  These and other predisposing factors are elaborated below.

Gastro-oesophageal reflux

This occurs when pressure in the stomach exceeds that in the lower oesophagus (eg from stooping, and with abdominal distension, pregnancy or obesity), or when the sphincter between the two relaxes, usually for short spells of between 5–30 seconds (Transient Lower Esophageal Sphincter Relaxation – TLESR). (2) Triggers for TLSERs include stomach distension, whether by swallowing air or taking large meals, (3) and again by stress manifested as heightened diaphragm activity.

Gastroparesis

Delayed gastric emptying is another digestive malfunction that exacerbates reflux and the frequency of TLESRs. Other symptoms include nausea, vomiting, abdominal pain, feeling full soon after beginning to eat and abdominal bloating. Causes of gastroparesis are elusive though it may be linked to immunological complications of viral infections, and interference in the vagus nerve in diabetes.

Hiatal hernia

This is marked by the lower oesophageal sphincter being forced upwards, to become separated from the diaphragm (which normally acts as the outer sphincter), the extent of this is directly linked to the levels of acid reflux and oesophagitis. HH appears to have no impact on TLESR rates but there is an extended acid pocket at the top of the stomach and reduced clearing of acid on swallowing. (4)

GORD (GERD)

When reflux is persistent it can lead to inflammation of the lower oesophagus (oesophagitis) which is widely referred to as Gastro-O/Esophageal Reflux Disease. GORD is a confusing syndrome, in fact usually diagnosed when symptoms are relieved by PPI acid-blockers like omeprazole! There are many different recognised subtypes. (5)

• Non-erosive reflux disease (NERD): An early stage of oesophagitis (often simply classified as heartburn), perhaps associated with hypersensitivity of the oesophageal mucosa.
• Erosive disease (classic GORD) increases in intensity (Los Angeles grade A, B, C or D) marked also by increasing damage to the oesophageal-gastric junction and likely hiatus hernia, more trouble when lying down, and association with gastroparesis.
• Barrett’s oesophagus: A condition seen as increasing the risk of oesophageal cancer, with endoscopy showing a spectrum, from non-dysplastic metaplasia through increasing grades of dysplasia. It is indicative of both acid and bile reflux and is associated with obesity, male gender, white ethnicity, smoking, and genetic factors.
• Reflux chest pain syndrome with pain indistinguishable from angina but resolved with antacid therapy.
• Regurgitation reflux disease with large volumes of reflux that is often difficult to manage.
• Reflux cough: Reflux is a common cause of chronic non-productive cough (and also asthma) and should always be checked for.

Stomach acid and gastrin

It is important to note that contrary to popular belief, stomach acid secretion is rarely abnormal in GORD. However as noted above for heartburn it is likely that the oesophageal mucosa becomes more sensitive to acid.  This is still enough rationale for the practice of reducing acid production to relieve GORD. Indeed gaining benefit from PPIs like omeprazole is as we have seen the main way GORD is diagnosed. Studies comparing the relative effectiveness of PPIs conclude that the fraction of the day that they maintain intragastric pH above 4 is a reliable marker of effectiveness in high grade oesophagitis, with the target being 50-70% of a 24 hour period. (6)

Gastrin is a stomach hormone that induces acid as well as stomach histamine production, and its levels have been proposed as a non-invasive marker of GORD. (7) The primary stimulus for gastrin secretion is the presence in the stomach of certain foodstuffs, especially protein peptides, certain amino acids and calcium. Also, as yet unidentified compounds in coffee, wine and beer can stimulate gastrin secretion. Gastrin levels can also rise in response to long-term suppression of acid production with antacids, and again as a rebound to coming off PPIs. They may also be raised in pernicious anaemia and when stomach-acid production capacity is reduced in atrophic gastritis.

After meals a layer of acid sits on top of the meal close to the oesophageal sphincter, ready to reflux. This is known as the “acid pocket” and is facilitated by the absence of peristalsis in the upper stomach.  The acid pocket is also more prominent in GORD and hiatus hernia.

Inflammation (or hypersensitivity?)

The conventional model of reflux esophagitis has been the “burn hypothesis” proposing that the caustic effects of stomach acid combined with enzymatic digestion by pepsin erodes the oesophageal epithelium. According to this paradigm, the easiest pathway for acid lies in the intercellular spaces, which are protected by proteins such as claudins, occludins, and E-cadherin. (8)

However, recent experiments have challenged this concept, instead proposing that much of the injury is chronic and chemokine mediated. (9) Among patients with GORD who discontinued PPIs 2 weeks before endoscopic biopsy, they found an increase in lymphocyte levels along with distended intercellular spaces in areas that were without surface erosions. (10) Specimens also stained positive for hypoxia-inducible factor (HIF) 2α, a proinflammatory cytokine that is induced by bile salts. Under this alternative paradigm, acid and bile salts enhance HIF-2α, leading to increases in levels of T-cell chemokines that promote oesophagitis. (11)

Helicobacter pylori

Epidemiologic data demonstrate that erosive oesophagitis and Barrett’s oesophagus are inversely related to H. pylori infection. The proposed protective mechanism is that chronic H. pylori infection leads to atrophic gastritis and relative hypochlorhydria (low acid production), which in turn diminishes the acidity of gastro-oesophageal reflux. (12,13)

Role of vanilloid (spice) receptors

Spice constituents like capsaicin, gingerols, piperine and curcumin stimulate transient receptor potential vanilloid-1 (TRPV1) receptors. These are present on oesophageal sensory nerve fibres. TRPV1 activation here has been found to occur with exposure to capsaicin as well as heat and acid. TRPV-1 expression is upregulated in patients with both oesophageal erosion and NERD. (14) The potential role of TPRV1 activation in inducing GORD symptoms was highlighted in a study in which submucosal injection of capsaicin and not acid triggered severe sensations of heartburn and chest pain in healthy volunteers. (15) With such activation, TRPV1 leads to nerve depolarization and may represent the primary nervous pathway for reflux symptoms.