The earliest studies of gastric acid and its digestive function were carried out by Dr. William Beaumont around 1830. Dr. Beaumont was a US Army surgeon who attended Alexis St. Martin, who sustained an accidental shotgun wound to the abdomen. St. Martin developed a gastric fistula through which Dr. Beaumont studied the effects of gastric acid on food. Dr. Beaumont’s observations led to the important discovery that stomach acid was essential for digestion. Dr. Beaumont also observed the relationship between gastric function and emotional state as the gastric mucosa would become engorged with blood in relation to St. Martin being upset or stressed [1]. Almost a century later, Johnston and Washeim [2] studied gastric acid secretion during sleep in normal subjects and described a rise in acidity, decrease in volume, and delayed gastric emptying. Later studies of the circadian rhythm of gastric acid secretion in healthy subjects indicated a peak in acid secretion between 10 p.m. and 2 a.m., and minimal acid secretion during wake time [3, 4]. These studies established that gastric acid secretion was very labile and altered not only by emotional state but also by state of consciousness and time of day. These observations laid the groundwork for our understanding of the pathogenesis of gastroesophageal reflux disease (GERD) and duodenal ulcer (DU) disease.

Prior to the discovery of the important role of Helicobacter pylori in the pathogenesis of DU disease, it was felt to be purely an acid-related disease and the healing of DU was felt to be closely related to the suppression of gastric acid secretion [5, 6, 7, 8]. The differential diagnosis and treatment of DU disease was detailed by Moynihan [9], noting that many patients had symptoms of nocturnal abdominal pain which were alleviated by food. The red stippling indicative of a DU was noted by Scudder in 1914 [10]. The stimulus for acid production is related to acid production secondary to vagal nerve stimulation. Vagotomy , or vagal sectioning, was introduced by Dragstedt in the late 1940s as an effective strategy for treating chronic DU disease theoretically caused by excessive vagal stimulation. Initially, the procedure was believed to reduce nocturnal secretion of gastric acid , which is generally elevated [11, 12, 13, 14] in DU patients. This is most likely due to a larger parietal cell mass, producing a larger acid output response to stimuli that provoke gastric secretion. Thus, the greater resting secretion in patients with DU compared to controls is thought to be caused by a normal basal drive acting upon a larger number of normally sensitive parietal cells [15, 16].

Other investigators were not able to support Dragstedt’s reasoning that vagotomy reduces basal secretions; instead, it was revealed that the procedure reduces histamine-stimulated secretion [17, 18, 19, 20]. A mechanism whereby vagotomy reduces histamine-stimulated gastric secretion has yet to be fully detailed, although multiple hypotheses have been offered for a sensitization phenomenon [21, 22] or the presence of more than one type of parietal cell responding to either histamine only, or both histamine and insulin (i.e., vagal) stimulation [23]. Nevertheless, Dragstedt’s vagotomy initiated decades of careful study of gastric secretory physiology and its effect on the etiology of ulcers , resulting in the notion that vagotomy reduces stimulated gastric secretion, predominately at night, allowing DU to heal.

In 1935, Winkelstein described the clinical entity of esophageal ulcers caused by gastric acid in patients with symptoms of substernal pain and heartburn [24]. Regurgitation of “peptic juice and its stagnation” [25] was demonstrated as the cause for esophagitis in the absence of comorbidities [25] . Subsequent observations have demonstrated that the condition of esophagitis is much more complex than a simple occurrence of acid contact with the esophageal mucosa. The pattern of esophageal acid contact has now been shown to be markedly different during the daytime compared to that during sleep. For example, as early as 1955 Lodge [26] commented on the importance of recumbency in the development of esophagitis.

The notion that sleep-related GER played a role in the development of esophagitis and other complications of GER emerged in the 1970s by the pioneering work of Johnson and DeMeester [27, 28]. Their work, which incorporated the new technology of 24-h esophageal pH monitoring, encouraged further investigation of the effect of sleep on GER and acid contact time. Indeed, these investigators noted that episodes of reflux occurring in the upright position, presumably during the waking state, are rapidly cleared. Episodes of reflux occurring in the recumbent position, presumably during sleep, are associated with markedly prolonged acid clearance. These studies effectively demonstrated the link between prolongation of acid clearance during the sleeping interval and the occurrence of esophagitis [27, 28]. During the same time period, Atkinson and Van Gelder [29] correlated the severity of esophagitis with the duration of nocturnal periods of high esophageal acidity. Collectively, these studies suggested that acid clearance is prolonged during sleep; however, none monitored sleep via polysomnography (PSG) and thus could not confirm this notion.

Orr and colleagues [30] conducted the first PSG study on patients with esophagitis and confirmed that acid clearance from the distal esophagus is prolonged during sleep in both healthy participants and patients with esophagitis, but more so in the esophagitis group. They also provided the additional insight that acid clearance is dependent on a brief awakening from sleep. Thus, patients who reflux during sleep were at greater risk to develop esophagitis [30, 31]. A later study by Robertson and colleagues [32] in which patients were monitored with a 24-h pH probe demonstrated that patients with complications of esophagitis have more severe acid reflux than patients with simple uncomplicated disease, and they concluded that this was likely due to prolonged periods of nighttime acid reflux. With this deeper understanding of the significance of prolonged acid contact time during sleep and its more complicated disease progression, a need for clinically differentiating sleep-related reflux and nighttime heartburn from daytime heartburn has become apparent.

Recognizing nighttime heartburn and associated sleep-related GER as a distinct clinical entity has been suggested in a recent review [33]. Data are reviewed to support the notion that recognizing the presence of nighttime heartburn encourages differential diagnosis and treatment options for GERD patients. Nighttime heartburn and sleep-related GER are considered a distinct clinical entity due to several factors reviewed by Orr [33] including: sleep-related GER is associated with prolonged acid mucosal contact which promotes mucosal injury, patients with nighttime heartburn are at greater risk of developing esophagitis, patients with nighttime heartburn have a higher incidence of extra-esophageal symptoms such as chest pain and cough, and patients with nighttime heartburn have significantly poorer quality of life. Two epidemiological studies have provided similar data which suggest that nighttime heartburn is a more serious and significant manifestation of GER compared to daytime heartburn [34, 35]. Furthermore, the majority of patients with nighttime heartburn (approximately 70 % in both studies) indicated that this symptom disrupted their sleep. Transient lower esophageal sphincter (LES) relaxation is frequently accompanied by GER and occurs postprandially in the daytime and in relation to brief or extended arousals from sleep in the nighttime [36, 37, 38]. Reflux events are less frequent during sleep likely due to inhibition of transient LES relaxation during deep sleep; however, they are typically associated with a marked prolongation in acid clearance [39, 40].

Responses to acid mucosal contact are quite different during sleep compared to responses measured during the waking state. Normal acid mucosal contact produces the waking sensation of heartburn, enhances salivary flow and bicarbonate concentration, and stimulates a higher frequency of swallowing [41]. These responses prevent prolonged acid mucosal contact by effectively removing the refluxate from the distal esophagus and neutralizing the mucosa. However, these responses are suppressed during sleep, resulting in prolonged acid mucosal contact [30, 31]. The subsequent back diffusion of hydrogen ions into the esophageal mucosa is related to the duration of acid mucosal contact [42]. Prolonged acid contact with the esophageal mucosa disrupts the normal barrier to the submucosa by increasing intercellular spaces allowing easier access of hydrogen ions [43, 44]. Thus, the longer reflux episodes noted during sleep carry a greater risk of producing mucosal damage compared to the more rapidly cleared reflux episodes during the waking state. Furthermore, one night of sleep deprivation has been shown to be hyperalgesic in patients with GERD [45]. Sleep-related acid contact time is a critical factor in the pathogenesis of the complications of GER including esophagitis, hiatal hernia, and other respiratory complications [46, 47]. Thus, clinicians may find it useful to assess symptoms of nighttime heartburn in differentiating patients who have a more serious form of GERD and experience more daytime sleepiness and a decline in work productivity [34, 35, 48, 49].

The discovery of the important role of Helicobacter pylori in the pathogenesis of ulcer disease has markedly changed the treatment of DU disease. However, acid production remains an important factor in the pathogenesis of DU and suppressing acid secretion remains important in the treatment of DU. Historically, vagotomy is credited with eliminating acid reflux for symptomatic relief of ulcers and the subsequent healing [5]. A nonsurgical approach was introduced in the 1970s utilizing histamine receptor (H2R) antagonists to suppress acid secretion [50]. Research in healthy volunteers indicated H2R antagonists inhibited gastric acid secretion [51–53]. Subsequent studies measured gastric secretion volume, pH, and hydrogen-ion concentration in 30-min intervals in patients with DU. A profound inhibition of nocturnal acid secretion was observed in patients with DU given H2R antagonists [54, 55]. Multiple daily doses versus a single bedtime dose of H2R antagonists have indicated the latter to be at least as good as the former in DU healing rates [56, 57, 58]. Maintaining a modest degree of nocturnal acid suppression alone has been shown to prevent the recurrence of DU disease [59]. Ulcers were found to heal and remain dormant with continued use of H2R antagonists, and as a result of this research, nocturnal acid secretion was thought to play a dominant role in the pathogenesis of DU.