Non-erosive reflux disease (NERD): GERD symptoms in the absence of visible esophageal mucosal injury during endoscopy; accounts for 70% of the GERD population [4,8,9].

Symptoms suggestive of GERD affect an estimated 30% of Western populations, and the prevalence continues to increase [11]. A comparison of GERD prevalence in different continents showed the highest rates in North America [11]. As noted, the prevalence of NERD in the GERD population is roughly 70% [12].

Among adult residents of Olmsted County, Minnesota (home of the Mayo Clinic), 18.1% had GERD (defined by at least weekly heartburn and/or regurgitation) [13]. Combining these data with results from three other U.S. studies with similar GERD definitions found a prevalence of 18.1% to 27.8% and a sample size-weighted average prevalence of 19.8% [11].

American studies conducted after 1995 show a significantly higher prevalence of GERD than studies conducted before 1995. Among various ethnicities, the incidence of GERD is higher in white individuals, likely related to lifestyle rather than genetic factors [8]. GERD incidence increases with age, especially after 40 years [4].

Gender differences are found across the GERD spectrum. Differences in GERD symptom expression have been suggested, with women more likely to have heartburn, regurgitation, belching, and extraesophageal symptoms than men [39]. Testing of subjects without reflux symptoms or GERD using ambulatory 24-hour esophageal pH monitoring, which evaluates esophageal acid presence, suggests women experience fewer reflux events, lower total reflux time, and fewer periods with pH <4 [40,41]. This suggests differences in upper GI response to reflux exposure, with greater sensitivity and symptoms in women despite less noxious acid exposure. However, men are more likely to develop pathologic changes of the esophagus [41]. Women are more likely to have partial response to PPIs, persistent GERD symptoms despite PPI treatment, and a need for PPI dose escalation [14,42,43].

In patients who meet the criteria for GERD, symptoms can impose a serious negative burden on quality of life. Disruptive GERD (more than once weekly symptoms) increases patient time off from work and decreases work productivity. These patients often have sleep impairment and decreases in physical functioning compared with patients with infrequent symptoms. Nocturnal GERD has a greater negative impact on quality of life compared with daytime symptoms. Nocturnal symptoms and sleep disturbances are critical to assess when evaluating the patient with GERD [15]. One nationwide survey of 1,000 adults with heartburn at least once a week found that 79% reported nocturnal heartburn. Of these respondents, 75% reported sleep disruption and 40% reported impaired functioning the next day. In addition, 71% were taking over-the-counter medications, but only 29% rated this approach as effective [16,44].

Predisposing factors for GERD include conditions that weaken the LES (e.g., hiatal hernia, pregnancy), increase pressure on the stomach (e.g., obesity, pregnancy, asthma), or affect transit of food from the stomach to the small intestine (e.g., diabetes, peptic ulcer disease, connective tissue disorders) [49].

Combining NSAIDs and selective serotonin reuptake inhibitors (SSRIs) increases the risk of upper GI bleeding greater than either drug alone. NSAIDs with SSRIs can markedly decrease serotonin platelet content, which impairs platelet aggregation in response to injury. This can prolong bleeding time, increase gastric acid secretion, and potentially promote ulcers and perforation. Combining SSRIs and NSAIDs should be avoided, if possible [63,64,65,66].

GERD is a chronic disease. Approximately 70% of patients with GERD experience chronic or relapsing symptoms and require long-term intermittent, on-demand, or continuous acid suppressant therapy, mostly with PPIs, while others may require antireflux surgery [59]. A large longitudinal population study found that among those with GERD at study initiation, GERD persisted for 10 years in 33% [76]. Patients with GERD followed clinically may have more severe and chronic illness than persons with GERD followed in the community. However, in a community study, the rate of chronic, unabated GERD was high and showed a substantial and persistent symptom burden.

GERD is widely assumed to arise from acid over-secretion. However, GERD symptoms can result from non-acidic reflux, and the core pathology in GERD involves impaired structure and function of the lower esophagus.

In parietal cells that line the stomach wall, proton pumps produce stomach acid by moving hydrogen ions from the parietal cell into the stomach lumen against a concentration gradient. Proton pump release of acid is prompted by signaling from acetylcholine, released by vagal nerve endings; gastrin, a local hormone produced by G cells in the antrum; and histamine, produced by enterochromaffin-like cells in the stomach wall [80]. Gastric acid kills micro-organisms, assists digestion, and facilitates absorption of iron, calcium, and vitamin B12 [81]. It also plays a crucial role in filtering out bacteria and in preventing development of enteric infections [82].

As discussed, GERD causes reflux esophagitis, reflux esophagitis causes Barrett esophagus, and the metaplasia of Barrett esophagus predisposes to esophageal adenocarcinoma. Until recently, the presumed cause of reflux esophagitis was caustic, chemical injury induced by acid and pepsin in reflux. Repeated exposure made the esophageal squamous epithelium permeable to acid, causing epithelial cell death that triggers a proliferative response to repair epithelial injury [87].

In addition to these cardinal symptoms, patients may display atypical symptoms and/or extraesophageal manifestations of GERD, including [8,50,79]:

Publications on the GERD diagnostic process increasingly point to the need for a more tailored approach, but the initial empiric PPI trial remains the standard of care.

Patients presenting with typical symptoms of GERD and no alarm features typically receive a presumptive diagnosis of GERD, confirmed by positive response to an empiric trial of PPI therapy. With a PPI trial, patients are prescribed once-daily PPIs for four to eight weeks. Nonresponders receive dose escalation to twice-daily PPIs for eight weeks. All PPI responders continue PPI therapy. Lack of response to a doubled dose of a PPI demands further objective evaluation [50]. The emphasis on the empiric PPI trial as a diagnostic and therapeutic tool is based on the premise that GERD symptoms and severity are proportional to exposure of esophageal tissue to acidic reflux. By targeting this core pathophysiology, response to PPI acid suppression therapy reliably confirms the diagnosis of GERD [1,79,107].

The empiric PPI trial has advantages of being simple, cost-effective, and, as stated, informative of whether further investigation is required [15,50,107]. The clinical approach that emphasizes the empiric PPI trial as a diagnostic and therapeutic tool has been endorsed by professional organizations including the American College of Gastroenterology (ACG), the American Gastroenterological Association (AGA), the American College of Physicians (ACP), the American Society of Gastrointestinal Endoscopy (ASGE), and the World Gastroenterology Organization [8,15,109,110,111].

Although empiric PPI trials have clear utility in ease and practicality, over-reliance has come under increasing criticism. This dissent centers on the diverse symptom profile and pathogenesis of reflux presentations that require management guided by symptom presentation and focused diagnostic testing instead of the uniform PPI trial approach [79]. A response to therapy would ideally confirm the diagnosis; however, this method is met with limited specificity (54%) and sensitivity (78%) [15]. A substantial placebo response is shown during empiric PPI trials, and PPI response widely varies by presenting symptom and underlying mechanism. This model has led to 30% to 60% of patients unsatisfied with their treatment, high levels of inappropriate PPI use, and failure to address visceral hypersensitivity, which amplifies symptom perception and complicates patient coping [79,112,113].

Endoscopy identifies and documents reflux-related esophageal mucosal damage; the presence and severity of reflux disease complications, such as erosive esophagitis, Barrett esophagus, or peptic ulcers; and anatomic abnormalities, such as hiatal hernia, masses, and strictures [116]. Upper GI endoscopy is the most common initial test in patients with GERD symptoms and PPI nonresponse and is performed urgently in patients with alarm features [1,117]. This procedure consists of an endoscope being fed down the esophagus into the stomach and duodenum, where a small camera sends video images to a monitor screen for close inspection of the esophageal lining [118].

GERD is diagnosed when endoscopy shows erosive esophagitis, and further testing is usually not needed. However, esophagitis is present in only 33% of patients with GERD symptoms and the absence of esophagitis does not rule out GERD. Patients with negative endoscopy should receive functional assessment [79].

Non-acid reflux is undetectable by standard pH monitoring but can induce symptoms in patients with GERD or functional esophageal disorders and is common in patients maintained on PPIs [52]. Impedance monitoring is a valuable test in patients with suspected GERD but negative pH testing, atypical or extraesophageal symptoms, or refractory GERD [4].

The AGA stresses the importance of considering hypervigilance, visceral hypersensitivity, and psychosocial distress when patients fail PPIs and diagnostic testing is negative. In any GERD symptom domain, these factors can exacerbate the primary symptoms and adversely impact patients' ability to cope with symptoms [79].

Diagnosis of NERD is made when there is evidence of abnormal esophageal acid exposure. When symptoms correlate with weakly acidic/non-acidic reflux events, the diagnosis is reflux hypersensitivity. Functional heartburn is diagnosed with normal esophageal acid and no symptom/reflux correlation. Diagnostic criteria are [7,128]:

Most commonly, patients are recommended to avoid foods that decrease LES pressure and to minimize behaviors that predispose to increased esophageal acid exposure [50]. In contrast to the extensive data on acid inhibiting medication in GERD, relatively few studies are published on lifestyle intervention [150]. Lifestyle modifications with the strongest evidence support are weight loss and head-of-bed elevation [50].

The ACG practice guidelines recommend H2RA use as a maintenance option in patients without erosive disease if patients experience heartburn relief [15]. A main limitation of H2RAs is tachyphylaxis (development of tolerance), often within two weeks of daily use. This pharmacologic phenomenon results in declining acid suppression and limits the regular use of H2RAs in clinical practice [160].

Once-daily PPIs for eight weeks heals reflux esophagitis in more than 80% of patients, and this is further improved by twice-daily dose escalation. Esomeprazole achieves higher short-term healing rates of reflux esophagitis than omeprazole, lansoprazole, and pantoprazole, but this advantage is negligible in less severe esophagitis. PPIs are effective for symptom relief in erosive and non-erosive disease, but efficacy in reducing regurgitation is considerably lower than with heartburn [169,170].

GERD practice guidelines and review papers often state that PPIs lack meaningful differences in potency. However, a comparative study of PPI efficacy in intragastric pH control, measured by percentage of time at pH >4 over 24 hours, found relative potencies, compared with omeprazole (1.00; reference), of 0.23 for pantoprazole, 0.90 for lansoprazole, 1.60 for esomeprazole, and 1.82 for rabeprazole [172]. This pharmacodynamic non-equivalence should be considered when prescribing or switching PPIs [62].

To achieve maximum response, it is important that patients receive correct instructions on how to use PPIs. The timing of PPI administration is essential. Patients are usually initiated on once-daily dosing, which must be taken 30 to 60 minutes before the first meal of the day, as the agents are most effective after a prolonged fast (i.e., overnight). Proton pumps are highly active during the postprandial period, and with a plasma half-life of one to two hours, PPIs reach peak concentration at the time of a meal [107,158]. If increased acid suppression is required, a second dose taken 30 to 60 minutes before the evening meal is more effective than doubling the morning dose [107].

With evidence that links long-term PPI use to potential risks, GERD practice guidelines recommend PPI dose reduction or discontinuation in some patients. In 2017, the AGA recommended that after a three- to six-month treatment course with good PPI response, patients with uncomplicated GERD should attempt to stop or reduce PPIs because patients who cannot reduce PPIs face the likelihood of lifelong PPI use [67]. In these patients, esophageal pH-impedance monitoring distinguishes acid-related disorders from a functional syndrome. The best candidates for this strategy may be patients with primarily atypical symptoms and those who lack obvious predisposition to GERD from central obesity or large (>3 cm) hiatal hernia.

Baclofen acts as an agonist of gamma-aminobutyric acid (GABA) type B receptors and is prescribed to decrease transient LES relaxation-related acidic and non-acidic reflux episodes [160]. Baclofen physiologically inhibits transient LES relaxations, and studies measuring baclofen effects with pH-impedance monitoring show significant reductions in postprandial acid- and non-acid-related symptoms in patients with heartburn by reducing transient LES relaxations, increasing LES tone, and decreasing reflux episodes. Studies have also demonstrated that baclofen reduces the number of postprandial and non-acid reflux events, nocturnal reflux activity, and belching episodes [50,52]. In patients with symptomatic GERD treated with daily omeprazole plus baclofen 10 mg or placebo, baclofen significantly reduced the rates of heartburn (46% vs. 4%) and regurgitation (54% vs. 4%) [201]. Baclofen may be particularly beneficial for patients with abnormally high non- or weakly-acidic reflux events [160]. However, baclofen requires adherence to twice or three times daily dosing, and common side effects include drowsiness, fatigue, and confusion [107].

Most PPI-refractory patients have NERD or functional symptoms, making treatment with pain modulators a reasonable option. Antidepressants are the most-studied medications for this indication and include tricyclic antidepressants (e.g., imipramine, nortriptyline), SSRIs (e.g., sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine), and trazodone. Doses used are lower than in depression, and randomized controlled trials have found them effective in reducing esophageal pain, especially in patients with esophageal hypersensitivity [210]. Antidepressants act by modulating the esophagus-brain axis. Patients with NERD and painful heartburn received functional magnetic resonance imaging (off-PPI) after 21 days of nortriptyline or placebo. Acid-induced activation in prefrontal cortex, caudate, insula, cingulate, and hippocampus brain areas were significantly reduced with nortriptyline compared with placebo [211].

Melatonin is an important signaling molecule in gut motility and gut-liver communication, and the esophageal mucosa possesses large numbers of melatonin-binding sites [60]. Exogenous melatonin is thought to control GERD symptoms by stimulating production of nitric oxide and prostaglandin E2, inhibiting gastric acid secretion, reducing inflammatory cytokines, and preventing acid/pepsin-induced esophagitis. Melatonin is not conventional therapy but may represent an alternative for patients lacking benefit from PPIs [50].

The body of published evidence demonstrates that MSA is an effective alternative to NFS [167]. Compared with NFS, five-year MSA outcomes showed comparable esophageal acid exposure, heartburn, regurgitation, PPI use, quality-of-life scores, and dysphagia, and lower rates of bloating and inability to belch or vomit [167,230]. MSA has the other advantages of being a less extensive surgical procedure, requiring minimally invasive removal, and less inter-surgeon variability with a standardized device. MSA is not indicated for patients with severe erosive disease, motility disorders, or large hiatal hernia (>3 cm) [167]. Negative predictors of excellent/good outcome with MSA include BMI >35, structurally defective LES, and elevated LES residual pressure [235].

Roux-en-Y gastric bypass (RYGB) remains the favored bariatric approach due to its benefit in GERD and long-term weight loss. Performed laparoscopically, RYGB involves creation of a small gastric pouch connected directly to the small intestine to bypass a major portion of the mid/distal stomach and duodenum [52]. A comparative study found laparoscopic RYGB as safe as fundoplication for morbidly obese patients. In-hospital complications were significantly lower in the bypass group, while the mean length of hospitalization, mortality, and treatment costs were comparable [239].