The Pathophysiology of GERD
The pathophysiology of acid reflux disease is very complicated. There is a tremendous imbalance between the defensive barriers which are protecting the esophagus and the aggressive factors rising from the stomach.
The defensive barriers are mechanical anti-reflux barriers, local tissue resistance and esophageal acid clearance. The attacking factors are gastric acidity and volume and duodenal contents including bile.
The intermittent nature of acid reflux symptoms and esophagitis in many patients suggests that the aggressive and defensive forces are part of a system which is delicately balanced.
Mechanical anti-reflux barriers
The first of the esophageal defences against stomach acid damage consists of the physical anti-reflux barriers. There is an anatomically complex region at the lower end of the esophagus. It includes the lower esophageal sphincter (LES), the diaphragmatic crura, the intra-abdominal location of the LES, the phren-oeso-phageal ligaments, and the acute angle of His.
The LES is a segment of lower esophagus about 3.0 – 4.0 cm in length. The LES is a high pressure zone between the esophagus and stomach. The LES is made up of muscles at the bottom of the esophagus as well as the muscles of the diaphragm (breathing muscle) that surround the bottom of the esophagus. When it is closed, the LES maintains a higher pressure than that of the stomach so that food and digestive juices cannot wash back into the esophagus. It is the major component of the anti-reflux barrier and is capable of preventing reflux even when it is completely displaced from the diaphragmatic crura because of a hiatus hernia.
The proximal (or upper) margin of the LES is normally about 1.5 –2.0 cm above the squamo-columnar junction, whereas the distal segment, about 2.0 cm in length, lies within the abdominal cavity. This location of the distal LES contributes to the maintenance of gastroesophageal competence during intra-abdominal pressure events.
There is considerable diurnal variation in basal LES pressure; it is lowest after meals and highest at night. It is also influenced by certain circulating peptides and hormones, foods (particularly fat), and numerous drugs, the most clinically relevant of which include theophylline, calcium channel blockers, estrogen, progesterone, and narcotics.
During swallowing, LES relaxation (LESR) occurs for 5 –10 seconds, thus permitting esophageal peristalsis to sweep the swallowed bolus into the stomach.Anatomically, the LES lies within the hiatus created by the right crus of the diaphragm, and it is anchored by the phreno-esophageal ligaments, which insert at about the level of the squamo-columnar junction.
The oblique entrance of the esophagus into the stomach creates a sharp angle on the greater curve aspect of the gastroesophageal junction. This is known as the angle of His. This angle is thought to create a flap-valve effect that contributes to gastroesophageal junction competency.
The Mechanisms of Reflux in GERD
Transient lower esophageal sphincter relaxations (LESRs) are the most common mechanism underlying acid reflux. They also account for the reflux of gases during belching.
Transient LESRs account for nearly all reflux episodes in healthy persons and for 50%– 80% of episodes in patients with GERD, depending on the grade of severity of associated esophagitis. But transient LESRs are not always associated with GER. In healthy people, about 40%– 60% of transient LESRs are accompanied by reflux episodes, compared with 60%–70% in patients with acid reflux disease.
The frequency of transient LESRs is increased by distension of the stomach. This is may be due to gas, a meal, or stress. Normally, meals are the major cause of transient LESRs, but which types of food cause these is not known. Temporary intermittent LESRs are reduced by lying flat, sleep and having a general anesthetic.
Various medications are known to impair transient LESRs. These including cholecystokinin A antagonists, anticholinergic drugs, morphine, somatostatin, nitric oxide inhibitors, 5-hydroxytryptamine 3 (5-HT3) antagonists, and GABA-B agonists.
About 5%–10% of reflux episodes occur during swallow-induced LESRs. Most of these episodes are associated with defective or incomplete peristalsis (muscular contractions that propel food down esophagus). Stress reflux occurs during coughing, bending or straining. Free reflux and stress reflux are two ways in which acid reflux can be associated with reduced LES pressure. Stress reflux happens when a relatively low pressure LES is opened wider by a sudden increase in pressure in the abdomen. E.g.when bending, coughing or straining.
Stress reflux is found mostly in patients who have severe esophagitis, in whom it may account for up to 23% of reflux episodes. It is rarely present in patients without endoscopic evidence of esophagitis. The mechanisms resulting in a low LES pressure are poorly understood.
The presence of a hiatus hernia reduces lower esophageal sphincter (LES) pressure because the inbuilt support of the crural diaphragm (breathing muscle between chest and abdomen) is lost.
According to gastroenterologists the relationship between hiatus hernia and GERD is controversial. The general opinion of specialists has shifted widely from one that virtually equated hiatus hernia with GERD to one that denied it a causal role. Currently, it is thought from research data that the hiatus hernia is important in patients with more severe esophagitis, peptic stricture, or Barrett esophagus. Hiatus hernias, identified by endoscope or x-ray studies, are reported in 54%–94% of patients with reflux esophagitis This rate is dramatically greater than that in the healthy population.
The functional impact of the hiatus hernia has been clarified by clever combined manometry and video-fluoroscopic studies, which show that hiatus hernia impairs LES function through several mechanisms as well as impairing esophageal clearance. Reflux is worse in patients who have a non-reducible as opposed to a reducible hiatus hernia.
The cause of hiatus hernia remains unclear. Familial clustering of acid reflux disease suggests the possibility of inherited muscle weakness in this area. Research has shown an association with lifting of heavy weights and obesity. This raises the possibility that, over time, chronic intra-abdominal pressure and stress may weaken the esophageal hiatus and may cause the development of a hiatus hernia. This theory is attractive because it helps to explain the fact that hiatus hernias become more common as people age. If you have a hiatus hernia it is important to follow a reflux diet.
Esophageal acid clearance
The second level of the esophageal defence against reflux damage is esophageal acid clearance. The frequency of episodes of reflux determine the times that stomach acid enter the esophagus, but esophageal acid clearance time determines the length of time that the mucosa is exposed to acid and probably the degree of acid damage. Esophageal acid clearance depends on two related but separate processes: volume clearance, which is the actual removal of the reflux material from the esophagus, and acid clearance, which is the restoration of normal pH in the esophagus after acid exposure through titration with alkaline base, rather than true removal of the refluxed stomach fluid.
Muscular waves of esophageal peristalsis help to clear the refluxed stomach acid in both the upright and supine positions, but they do not work during deep rapid eye movement sleep. Primary peristalsis is precipitated by swallowing, which occurs at a frequency of about once per minute in people who are awake. This is regardless of whether reflux occurs. Secondary peristalsis, initiated by esophageal distension from acid reflux, is much less effective in promoting clearance of refluxed stomach acid and therefore offers only an ancillary protective role.
Poor peristaltic function, in other words, failed peristaltic contractions and low pressure (< 30 mmHg) peristaltic contractions that incompletely empty the esophagus, increases in frequency with the degree of esophagitis. Failed peristalsis results in very poor volume clearance because the feeble contractions clear most, but not all, of the stomach acid from the esophagus. Whether esophagitis leads to peristaltic dysfunction or whether an underlying motility disorder predisposes to the development of reflux disease is not known.
The force of gravity contributes to bolus clearance when reflux occurs in the upright position. At night, when patients are lying flat, this mechanism is not operative unless the head of the bed is elevated. This long used and helpful treatment of GERD does improve the flow of refluxed stomach acid back into the stomach time. It is most beneficial in those patients with total failure of peristalsis (e.g. in those with a condition called scleroderma).
Salivary and esophageal gland secretions
Saliva is the second vital element required for normal esophageal clearance of acid. Saliva has a pH of 6.4 –7.8 and therefore is a weak alkaline compared with the acidic gastric contents. The importance of swallowed saliva is confirmed by findings that increased salivation induced by oral lozenges is associated with a significant decrease in acid clearance time. Physiological or pathological compromise of salivation may contribute to GERD. Diminished salivation during sleep explains why nocturnal reflux episodes are associated with markedly prolonged acid clearance times.
Cigarette smoking may promote acid reflux. This was originally attributed to the effects of nicotine on lowering LES pressure, but more recent studies suggest that cigarette smokers have reduced saliva production. This may also prolong esophageal acid clearance.In addition to the role of saliva, dilution and neutralization of residual refluxed acid are aided by the watery bicarbonate rich secretions produced by the sub-mucosal glands of the esophagus. The reflux of acid into the esophageal lumen stimulates these glands and helps to neutralize the acid, even if swallowing does not take place.
The above described clearance mechanisms minimize acid contact time with the epithelium. But even in healthy people the esophagus may be exposed to acid for 1–2 hours during the day and sometimes at night. Despite this only a few people experience symptomatic gastro-esophageal reflux and even fewer suffer GERD. This is because of the third level of esophageal defence, known as tissue resistance.
Tissue resistance is not a single factor but a group of dynamic mucosal structures and functions that interact to minimize mucosal damage from the noxious stomach contents.Unlike the stomach, in which superficial mucosal injury is repaired in hours, the esophagus repairs itself more slowly over days to weeks.
Gastric factors (especially gastric volume and certain aggressive factors found in the stomach juices) seem to be potentially very important in the production of reflux esophagitis.
The gastric volume is determined by the actual rate of acid secretion , whether there is also Helicobacter pylori infection, by the degree of reflux from the duodenum into the stomach, and the rate of gastric emptying. Increased gastric volume not only results in more gastric contents being available for reflux but also increases the rate of transient LESRs.
Gastric acid secretion: Stomach acid is of primary importance in the production of reflux esophagitis, but the way it causes damage action may involve activation of pepsin(a digestive enzyme produced by the stomach lining) rather than direct damage from acid on its own. Research in animals has shown that acid causes minimal injury at a pH of less than 3.0, primarily by breakdown of of protein molecules. However, the combination of acid and even small amounts of pepsin disrupts the mucosal barrier resulting in increased H+ ion permeability, histological changes, and gross haemorrhage. In other words acid and pepsin together produce much more tissue damage than acid alone. In addition to the animal studies, a series of clinical reports showed that patients with various grades of esophagitis, including Barrett esophagus, have an increased frequency and duration of esophageal exposure to gastric juices of pH lower than 4.0. In contrast, exposing the esophagus of animals with a pepsin solution of pH 7.5 produces only slight damage to the esophagus. These important findings explain why acid suppression treatment is so effective in the treatment of acid reflux disease.
Some research studies have suggested that those patients with reflux, especially those who respond poorly to conventional anti-secretory therapy, may have higher rates of acid secretion than control patients. But, most studies have found no abnormality of gastric acid secretion in patients with GERD. Factors that reduce gastric acid secretion naturally, for example concomitant infection with Helicobacter pylori, especially if it is the virulent cagA+ type, may protect from the development of severe esophagitis and Barrett esophagus. Helicobacter pylori, particularly this virulent strain, is a biological anti-secretory agent that lowers gastric acidity. It produces severe gastritis of the stomach body and accelerates the progression to multifocal atrophic gastritis and intestinal metaplasia, with concomitant lower acid output. In addition, the bacteria produce ammonia, which acts as a powerful neutralizing agent under elevated pH conditions. The lining of the stomach body returns to normal when the Helicobacter pylori infection is cured, increasing acid secretion and possibly contributing to the reports of esophagitis following successful treatment of Helicobacter pylori infection. The consequences of the return to normal of parietal cell function and return to higher levels of stomach acid are unknown, but they could lead to the development of more severe GERD, Barrett esophagus, and adenocarcinoma in Western populations.
Bile acids that reflux from the duodenum have long been implicated in the development of esophagitis, especially when reflux of bile from the duodenum into the stomach is increased. Studies in animals have shown that conjugated bile acids produce much greater damage when combined with acid and pepsin. In contrast, trypsin, de-conjugated bile salts, and the conjugated bile salt taurodeoxycholate are more damaging in the absence of acid.
Research has shown that acid reflux and bile reflux increase together across the spectrum of GERD, making it nearly impossible to incriminate one agent over the other in the development of esophagitis. In addition aggressive acid suppression with proton pump inhibitors (PPIs) decreases both acid and duodeno-gastric reflux, probably by decreasing the volume of gastric contents which is available to move up into the esophagus. Finally, the absence of evidence of bile deposits in human esophageal biopsies refutes an important role for bile salts in acid reflux disease.
Delayed gastric emptying
The importance of delayed emptying of the stomach in the development and pathogenesis of acid reflux disease is controversial. Nevertheless delayed gastric emptying may be a major factor contributing to GERD in some groups of people, such as those diabetic patients with autonomic peripheral neuropathy.
Associated medical conditions
Certain medical and surgical conditions can increase a person’s risk of developing acid reflux disease. The most common of these is being pregnant. About 30%–50% of pregnant women have symptoms of heartburn, especially in the first trimester. Pregnancy increases the risk of reflux because of the relaxing effects of the increased levels of the circulating hormones estrogens and progesterones on LES pressure. Although symptoms of heartburn may be severe, esophagitis is uncommon. If you are pregnant following a gerd diet will ease the symptoms of heartburn.
Up to 90% of patients who have the condition scleroderma will develop GERD as the result of smooth muscle fibrosis that leads to a low LES pressure and weak or absent peristalsis. Severe disease is common in scleroderma. Up to 70% of patients have esophagitis, many have peptic strictures, and Barrett esophagus and carcinoma of the esophagus have been reported.
Unlike the previous two conditions, which are characterized by LES dysfunction, greatly increased secretion of acid and increased gastric volume are the major factors causing GERD in patients who have the Zollinger–Ellison syndrome. In these patients, the esophagitis and complications may be more difficult to treat than the ulcer disease. After Heller myotomy, about 10%–20% of patients may develop acid reflux disease. Finally, prolonged naso-gastric tube intubation may lead to the development of reflux esophagitis, partly because acid tracks along the tube and partly because the tube mechanically interferes with LES barrier function.