There are limitations to epidemiologic estimates of the prevalence of NERD due to the spectrum of symptoms, low sensitivity of low grades of erosive esophagitis (especially Los Angeles Grade A), widespread use of proton pump inhibitors, and evolving definitions. Early studies reported that about 50% of patients with heartburn were found to exhibit normal esophageal mucosa during endoscopy [13, 14]. However, several European community-based studies found a much higher prevalence of up to 70% [15, 16]. Robinson et al. evaluated subjects who used antacids for symptomatic relief of heartburn. Of 165 patients enrolled in this study, 53% had normal esophageal mucosa on upper endoscopy [17]. In a population-based study, 1000 subjects with or without GERD-related symptoms were randomly selected to undergo an upper endoscopy. Of the patients with gastroesophageal reflux symptoms, only 24.5% were found to have erosive esophagitis [18]. Zagari et al. performed a similar large epidemiologic study in the general population in northern Italy. Of the patients with reflux symptoms, 75.9% were found to have a negative endoscopy [19]. Based on a review of two population-based studies, one non-community study, and several endoscopy-based studies, 50–85% of patients with typical reflux symptoms have NERD [20]. It was also estimated from this review that 11–12% of the general population and considerably higher proportions of patients presenting to endoscopy (37–87%) may have NERD. In Asia, NERD is the most common presentation of GERD, affecting up to 65% of Indians, 72% of Malaysians, and over 90% of Chinese in studies from Malaysia, Singapore, China, and Hong Kong [21]. In a cross-sectional study analyzing 10,837 healthy Japanese subjects who underwent upper gastrointestinal endoscopy, 733 (6.8%) had reflux esophagitis and 1722 (15.9%) had NERD. In a recent retrospective study including 3382 patients with heartburn symptoms, 59% had NERD and 41% had erosive esophagitis [22]. Overall, based on old and recent epidemiologic studies investigating patients with GERD-related symptoms, the prevalence of NERD in the general population is between 50 to 70%.

The pathophysiological relationship between NERD and erosive esophagitis or Barrett’s esophagus remains the subject of protracted debate [23], with most studies demonstrating a low, if any, rate of progression from NERD to erosive esophagitis and Barrett’s esophagus. Most of the studies are limited because of retrospective design, irregular follow-up, and common use of antireflux medication in GERD patients.

Pace et al. followed 33 patients with NERD retrospectively for a period of 3–6 months while on therapy with antacids, prokinetics, or both [24]. Five (15%) of the patients that remained symptomatic during therapy developed erosive esophagitis of unknown grading. However, there were several limitations to this study. Patients were treated from the time of admittance into the study, suggesting that some may not have been true NERD patients. Furthermore, since it was noted that NERD patients rapidly progressed to develop erosive esophagitis after only a very short duration of follow-up (3–6 months), this may indicate that those who developed erosive esophagitis during the study period were likely healed erosive esophagitis patients that were labeled incorrectly as having NERD from the beginning.

Kuster et al. followed 109 patients with GERD, of whom 33 had endoscopically documented erosive esophagitis for 6 years [25]. Only 2.7% of the NERD patients developed erosive esophagitis after 3 years and 3% after 6 years of follow-up. This study provided longer duration of follow-up, and despite its limitations (i.e., high dropout rate) very few NERD patients progressed to develop erosive esophagitis. Isolauri et al. conducted a longer duration follow-up (17–22 years, mean 19.5 years) of 60 patients with documented GERD [26]. Patients received medical (N = 50) or surgical (N = 10) antireflux therapy as needed (no standardization). Of the subjects who received only medical therapy, 30 had NERD and 20 had erosive esophagitis at baseline. At follow-up, only five (17%) of the NERD patients progressed to erosive esophagitis (all to grade 1 Savary-Miller).

McDougall et al. performed a prospective follow-up of 101 GERD patients for a period of at least 32 months after initial assessment with pH testing and an upper endoscopy [27]. During follow-up more than half of the patients were on a PPI or H₂ blocker. Of the 17 subjects with NERD and abnormal pH testing, 4 (24%) developed erosive esophagitis while on an H₂ blocker. In a 5-year follow-up investigation including patients with NERD (N = 113) and erosive esophagitis (N = 90) at baseline, progression from NERD to erosive esophagitis occurred in 11 patients and 2 developed Barrett’s esophagus [28].

One study stands out in their findings about the natural course of NERD. In a publication by Pace et al., which was a long-term follow-up of a previously published short-term follow-up study, the authors claimed that 94% of NERD patients progressed to develop erosive esophagitis after 5 years [29]. The authors concluded that GERD is a chronic disease characterized by increasing severity over time, requiring protracted medical therapy, and that almost all NERD patients are destined to progress to erosive esophagitis, regardless of the extent of their esophageal acid exposure. However, in their original study, Pace et al. included a large number of patients with healed erosive esophagitis [24], who were erroneously considered as having NERD. Their original article lacks any information on how the diagnosis of NERD was made, what grading system was used to describe esophageal mucosal involvement, and whether patients were receiving any antireflux treatment prior to first endoscopy.

Labenz et al. have proposed a highly complex model to describe the natural course of GERD [30]. The authors evaluated progression or regression in GERD using the ProGERD (progression of gastroesophageal reflux disease) database. After a 2-year follow-up, 24.9% of the NERD patients progressed to develop low-grade erosive esophagitis (Los Angeles classification grades A and B), and 0.6% developed severe erosive esophagitis (Los Angeles classification grades C and D). Interestingly, 50.4% of the subjects with grades C and D and 61.3% with grades A and B regressed to NERD. The study provides findings from only two endoscopic studies (index and follow-up). This is the first study that suggests that patients may move freely and in large numbers from NERD to erosive esophagitis and back again.

Serrano et al. followed 692 GERD patients over a period of 6 years and prospectively assessed progression or regression along the spectrum [31]. Patients with NERD did not develop erosive esophagitis and those with erosive esophagitis remained within the grading of the initial diagnosis. Sontag et al. performed a retrospective study of 2306 GERD patients having at least two separate upper endoscopies during a mean follow-up of 7.6 years. The authors reported that the endoscopic findings of 67% of the patients remained unchanged, 21% improved, and 11% worsened [32]. Bardhan et al. provided the longest and largest natural history data evaluating 12,374 GERD patients over a period of 24 years [33]. The authors documented only 4.4% progression to erosive esophagitis among the NERD patients with the mean time for the development of this change being 5.3 years. In a separate study, male sex, smoking, and presence of metabolic syndrome independently increased the likelihood of progression from NERD to erosive esophagitis [34].

Thus far, there is no evidence to suggest that patients with NERD progress to adenocarcinoma of the esophagus. In a recent large population-based cohort study of 33,849 patients, only erosive esophagitis was associated with an increased risk of adenocarcinoma of the esophagus [35]. Of the 7655 patients with NERD, only 1 was diagnosed with adenocarcinoma of the esophagus after 4.5 years of follow-up.

Overall, these studies suggest that lack of progression is much more common than progression along the spectrum of patients with NERD. The vast majority of NERD and erosive esophagitis patients remain within their respective GERD group throughout their lifetime (Fig. 10.3) [36]. Most importantly, there is no evidence that NERD patients progress over time to develop Barrett’s esophagus or adenocarcinoma of the esophagus.

Current concepts in the pathophysiology of NERD involve peripheral factors (luminal, mucosal, and sensory afferents) as well as central (psychological, stress, sleep, etc.).

Overall, there is no difference in gastric acid output between NERD patients and those with erosive esophagitis [37]. The degree of esophageal acid exposure in patients with NERD is significantly lower as compared to that measured in patients with erosive esophagitis or Barrett’s esophagus. In one study, the mean recorded number of acid reflux events was 95.3 in NERD versus 139.7 in those with erosive esophagitis [10]. Furthermore, patients with NERD have the lowest esophageal acid exposure profile (pH < 4) in % total, recumbent, and upright time as compared to the other GERD groups. Unlike patients with erosive esophagitis and Barrett’s esophagus who demonstrate a very high acid exposure in the very distal portion of the esophagus that tapers down proximally, NERD patients have very little variation in esophageal acid exposure distribution throughout the esophagus (total and recumbent) [38]. Shapiro et al. have shown a marked overlap in esophageal acid exposure between NERD patients and those with erosive esophagitis and even those with Barrett’s esophagus (Table 10.1) [39]. The study suggests that other factors, possibly genetic and environmental, determine disease presentation.

Recently, Sano et al. evaluated the mechanisms of acid reflux episodes in patients with NERD as compared to healthy controls and patients with mild esophagitis [40]. Transient lower esophageal sphincter (LES) relaxation (TLESR) was found to be the major mechanism of acid reflux in all three groups. There were no differences in the rate of TLESRs per hour among the three groups. At 7 cm above the LES, patients with NERD had significantly more frequent episodes of acid reflux during TLESRs (mean ± SEM 42.3 ± 4.8 per hour) as compared to those with mild reflux esophagitis (28.0 ± 3.8 per hour) and healthy subjects (10.8 ± 2.5 per hour) suggesting that acid extends proximally more readily in patients with NERD than in the other two groups. Furthermore, total acid and weakly acidic reflux is greater in erosive esophagitis and Barrett’s esophagus than in NERD [41], but NERD patients demonstrate greater proximal migration of any type of reflux [38]. NERD patients are also more sensitive to weakly acid reflux than those with erosive esophagitis [42].

Adachi et al. have demonstrated that NERD patients had significantly lower nighttime esophageal acid exposure as compared to patients with grade C and D erosive esophagitis [43]. Dickman et al. have shown that the esophageal acid exposure pattern during sleep is similar among the different GERD groups [44]. NERD patients with abnormal pH test had similar level of esophageal acid exposure during sleep as patients with erosive esophagitis. Esophageal acid exposure was the highest at the beginning of sleep and markedly dropped toward the middle of the sleep period.

Several luminal factors were found to be predictive of a sensed acid reflux event as compared to a non-sensed acid reflux event (using impedance + pH sensor), and they include proximal migration of an acid reflux event, larger pH drops, lower pH nadir, larger volume and longer acid clearance time, preceding higher esophageal cumulative acid exposure time, and presence of gas in the refluxate [42, 45]. Schey et al. have shown that NERD patients demonstrated the highest number of acid reflux events before a sensed reflux event as compared with other heartburn groups [46]. This suggests that prior sensitization is needed for an acid reflux to be perceived in NERD patients who demonstrated a lower esophageal acid exposure compared with erosive esophagitis patients. Proximal esophageal migration of a reflux event has been shown to be an important predictor of symptom generation in NERD patients as well as other GERD groups, regardless of whether the reflux is acidic or weakly acidic [47]. The underlying mechanism for this phenomenon is unknown. Some have stipulated that it is likely due to summation effect (the higher in the esophagus the reflux migrates, the more esophageal pain receptors are sensitized) or increased sensitivity of the proximal portion of the esophagus to either chemical or mechanical stimuli.

The role of nonacid reflux in NERD was assessed by esophageal impedance-pH monitoring in 150 NERD patients [48]. NERD patients had more reflux episodes (acid and nonacid) as compared to controls. A study that was conducted in a small group of normal subjects has demonstrated that acidic or weakly acidic solutions can result in the development of dilated intercellular space (DIS) [49]. The study suggests that NERD patients are likely to develop similar mucosal abnormalities from both types of gastroesophageal reflux. DIS in NERD patients have been associated with impaired esophageal mucosal resistance [49, 50]. Farre et al. found baseline impedance as a sensitive marker of esophageal mucosal integrity in a rabbit model [51]. In a systematic review of patients with GERD who are on a PPI, 80% of reflux episodes were weakly acidic or weakly alkaline and 83% of symptom episodes were associated with weakly acidic or weakly alkaline reflux. The study concluded that weakly acidic reflux underlies the majority of reflux episodes in patients with GERD on PPI therapy, and is the main cause of symptoms occurring on PPI therapy [52]. A recent study demonstrated that symptomatic weakly acidic refluxes were preceded and sensitized by acid reflux episodes [53].

Gas reflux episodes can be perceived as heartburn and regurgitation [45] by triggering mechanoreceptors during esophageal luminal distention [54]. Emerenziani et al. demonstrated that the presence of gas in the refluxate significantly increases the probability of reflux perception in NERD patients [42]. Moreover, a recent study showed that some patients with GERD symptoms refractory to PPI therapy have increased number of prandial air swallows and postprandial, mixed gas-liquid reflux than those who responded to PPI therapy [55].

There are very limited data concerning the role of bile reflux in symptom generation of patients with NERD. The mean fasting gastric bile acid concentration in NERD patients is similar to healthy controls. Additionally, combined acid and duodenogastroesophageal reflux, which correlates with severity of mucosal involvement in GERD, has been documented in only 50% of NERD patients compared with 79% of erosive esophagitis patients [56].

Physiological studies in patients with NERD have revealed minimal esophageal abnormalities. These patients have a slightly higher rate of primary peristalsis failure, defined by non-transmitted contractions or peristaltic contractions that do not traverse the entire esophageal body as compared to normal controls [57]. The rate of triggering secondary peristalsis in patients with NERD is significantly lower than normal controls. However, when secondary peristalsis does occur in NERD patients, there is no difference in amplitude and velocity when compared to normal controls [57]. The abnormality in secondary peristalsis may explain the overall homogeneous distribution of acid reflux that was observed by Dickman et al. [38]. NERD patients demonstrate mildly reduced mean lower esophageal sphincter resting pressure and distal amplitude contractions as compared with normal subjects [58]. Resting lower esophageal sphincter pressure is rarely below 10 mm Hg [23]. In contrast, 25% of patients with mild erosive esophagitis and 48% of those with severe erosive esophagitis demonstrate peristaltic dysfunction. The mean resting lower esophageal sphincter pressure is significantly lower in patients with erosive esophagitis as compared to those with NERD [23, 37].

Hiatal hernia occurs in only a minority of NERD patients. Cameron et al. compared hiatal hernia rates in patients with NERD versus those with erosive esophagitis and demonstrated that 29% of the NERD patients had hiatal hernia as compared with 71% of those with erosive esophagitis [59]. A recent study showed hiatal hernia in 34.5% of patients with erosive esophagitis as compared to 17.4% of NERD patients [60]. The absence of diaphragmatic hernia suggests that transient lower esophageal sphincter relaxation is likely the predominant mechanism for gastroesophageal reflux in most of the NERD patients [40, 61].

The main underlying mechanism for heartburn is sensitization of esophageal chemoreceptors either directly by gastroesophageal reflux or indirectly by inflammatory mediators [62]. Dilated intercellular space (DIS) has been suggested to be an indicator of early diagnosis of GERD [63, 64]. It has been proposed that this physiologic event is possible related to the presence of marked DISs in the esophageal mucosa of NERD patients, as documented by electron microscopy. The presence of DISs results in an increase in paracellular permeability, allowing acid and other reflux components to diffuse into the intercellular spaces and reach nerve endings that are located within the esophageal mucosa, leading to a heartburn sensation [65].

It still remains to be elucidated why most acid reflux events (95%) that occur during a 24-h pH test are not associated with symptoms. It has been substantiated that acid is not the only stimulus responsible for heartburn sensation, but rather one of a host of different intraesophageal stimuli (nonacidic reflux, a motor event, distension etc.).

Visceral hypersensitivity has also been considered to be an important pathophysiological mechanism in NERD. Three broad mechanisms are believed to underlie visceral hypersensitivity: peripheral sensitization, central sensitization, and psychoneuroimmune interactions [66]. In general, assessment of esophageal sensitivity in NERD patients has yielded evidence for reduced perception thresholds for painful stimuli. However, results are difficult to compare due to different sensory testing protocols as well as differences in stimuli. Furthermore, many studies evaluated so-called NERD patients without excluding the functional heartburn group.

Miwa and colleagues have specifically evaluated stimulus response functions to acid in patients with NERD, as compared to other GERD groups, using an acid perfusion paradigm [67]. The authors demonstrated that NERD patients had lower perception thresholds for pain, especially as compared to normal controls, but also as compared to those with erosive esophagitis and Barrett’s esophagus. In a subsequent study, the authors confirmed their previous results but also noted that NERD patients were more sensitive to saline than subjects with erosive esophagitis [68]. The authors concluded that NERD patients display a more general esophageal hypersensitivity that is not limited to acidic stimuli only. Even when compared to functional heartburn, NERD patients with abnormal pH testing demonstrated lower perception thresholds for pain using a similar acid perfusion paradigm [39]. It has been proposed that the functional heartburn group, as compared to NERD patients, is a heterogeneous group composed of patients with esophageal hypersensitivity in which some are sensitive to chemical stimuli (acid) and others to different stimuli (thermal or mechanical).

Mechanical and thermal stimulation of the esophagus was also assessed in NERD patients. In a study by Reddy et al., the authors used a multimodal stimulation probe to assess pain evoked by either thermal or mechanical stimuli [69]. NERD patients demonstrated increased esophageal sensitivity only to heat stimuli but not to cold or mechanical stimuli when compared to normal controls. However, other studies have also demonstrated an increased sensitivity to mechanical stimuli (balloon distention) in NERD patients when compared to the other GERD groups [70]. Various central mechanisms have also been shown to influence processing of afferent signals at the brain level [71]. Psychological stress and emotional perturbation have been demonstrated to potentiate perception of intraesophageal stimuli [72].

Several receptors have been identified as mediating esophageal hypersensitivity due to acid, including acid-sensing ion channels, TRPV1 receptors (transient receptor potential vanilloid type 1), TRPV4- and the TRPA1-receptor, purinergic (P2X) receptors, and prostaglandin E-2 receptor (EP-1) [54, 73, 74]. Ma et al. demonstrated that TRPV1 activation causes ATP release from esophageal epithelial cells which results in release of substance P and calcitonin gene-related peptide from esophageal submucosal neurons and upregulation of platelet-activating factor (PAF) by the epithelial cells [75]. Release of PAF induces production of inflammatory mediators in the circular muscle layer which decrease muscle contraction, possibly leading to a self-sustaining cycle of motor abnormalities, resulting in enhanced exposure of the mucosa to acid and further inflammation. Furthermore, both PAF and substance P are important inflammatory mediators which could lead to an increased mucosal permeability and further peripheral sensitization [75].

Currently there are no clinical features that can distinguish patients with NERD from those with erosive esophagitis, Barrett’s esophagus, reflux hypersensitivity, or functional heartburn. Studies have consistently demonstrated that the severity, frequency, or intensity (severity × frequency) of symptoms is similar among the different GERD phenotypes and heartburn-related functional esophageal disorders [76]. The impact of heartburn severity on patients’ quality of life was similar in patients with NERD and those with erosive esophagitis [76, 77].

Several studies evaluated the clinical characteristics of NERD patients. Lind et al. conducted a large study consisting of 424 patients with troublesome heartburn associated with NERD [15]. The mean age of the population was 50 years; 58% were female; 21% were smokers; 45% were active alcohol users; 53% had more than a 5-year history of heartburn; and 37% had hiatal hernia documented during upper endoscopy. Carlsson et al. compared the clinical characteristics of patients with NERD and those with erosive esophagitis [77]. In the NERD group, 60% were female; the mean age was 49 years; mean weight was 80.5 kg for males and 69.5 kg for females; 23% were smokers; 59% were alcohol consumers; 80% had symptom duration longer than 12 months; 29% had hiatal hernia; and 34% were positive for Helicobacter pylori . The erosive esophagitis group was similar to the NERD group when comparing mean age, smoking, alcohol consumption, prevalence and duration of heartburn, and Helicobacter pylori status. However, there were more males (59%), increased prevalence of hiatal hernia (56%), and increased weight of both males and females (86 kg and 76 kg, respectively) in the erosive esophagitis group. Lee et al. also compared symptom presentation and risk factors for NERD and erosive esophagitis in 261 Chinese patients [60]. The erosive esophagitis group was significantly older (mean 48.94 vs. 43.34 years) predominately male (58.6 vs. 39.5%), had more hiatal hernia (34.5 vs. 17.4%), greater body weight (67.57 vs. 61.06 kg), and higher BMI (24.09 vs. 22.68) than patients with NERD. Both erosive esophagitis and NERD groups had similar rates of severity and frequency of heartburn and acid regurgitation and lifestyle habits (such as tea, coffee, alcohol consumption, and cigarette smoking). While the frequency of regurgitation was significantly greater in the female NERD patients than in the male NERD patients, this was not noted with heartburn symptoms. GERD symptoms and quality of life for the erosive esophagitis and the NERD groups were similar and both groups had lower quality-of-life scores when compared with the control group. The female patients with NERD had a higher frequency of GERD symptoms and lower quality-of-life score as compared with the NERD male patient. Gender had no effect on symptom scores or quality-of-life scores in the erosive esophagitis group. A recent study evaluating risk factors for erosive esophagitis and NERD demonstrated that a hiatal hernia increased the risk for both erosive esophagitis and NERD. Helicobacter pylori infection was significantly more common among those with NERD. Logistic regression analysis showed that female gender was a significant risk factor for NERD [22].

Increase in body mass index (BMI) has been associated with an increased risk for having erosive esophagitis or other complications of GERD [78]. However, a recent study has demonstrated that being overweight is an important risk factor for having NERD but not reflux hypersensitivity or functional heartburn [79].

Psychological comorbidities in GERD patients have been shown to predict the presence of GERD-related symptoms regardless of the presence or absence of esophageal mucosal injury [80–82]. Patients with higher emotional sensitivity or neuroticism complain more frequently of GERD symptoms such as heartburn. However, studies did not find a specific correlation between psychological comorbidity and esophageal mucosal damage or extent of esophageal acid exposure [83].

Wu et al. evaluated the clinical characteristics of patients with NERD in comparison to those with erosive esophagitis [84]. Each patient underwent endoscopy, esophageal manometry, acid perfusion test, and ambulatory 24-h esophageal pH monitoring. The authors found that NERD patients had a significantly higher prevalence of functional bowel disorders such as functional dyspepsia and irritable bowel syndrome. In addition, NERD patients were more likely to have psychological disorders and positive acid perfusion test. In contrast, patients with erosive esophagitis were characterized by higher prevalence of hiatal hernia, greater esophageal acid exposure, and more esophageal dysmotility [85].

Irritable bowel syndrome (IBS) and dyspepsia-like symptoms are commonly reported by NERD patients [84, 86]. However, the association or overlap with functional bowel disorders is not unique to NERD and is also very common in erosive esophagitis patients. These symptoms were demonstrated to independently determine reflux symptom severity in NERD patients as compared with normal controls [87]. A recent study evaluated upper gastrointestinal symptoms (GERD and dyspepsia-like) in patients on maintenance PPI therapy for erosive esophagitis or NERD [88]. NERD patients had significantly higher symptom scores than the erosive esophagitis group. In a study comparing NERD and functional heartburn patients by assessing bowel symptoms, heartburn was scored higher in patients with NERD as compared to those with functional heartburn, while bowel symptoms were similarly scored in the two groups. In both functional heartburn and NERD, bowel symptoms were the strongest predictors of heartburn severity [89].

Several studies have reported that GERD is commonly associated with sleep disturbances resulting in considerable economic burden and reduction in health-related quality of life [90, 91]. Sleep dysfunction has been shown to be similar in patients with NERD and those with erosive esophagitis [92]. Although the causative relationship between GERD and OSA remains a subject of debate, a recent study conducted by You et al. found that there was an increased risk for OSA in patients with NERD as compared to patients with erosive esophagitis and healthy controls [93]. Furthermore, subjects with nocturnal GERD-related symptoms in the NERD group were more commonly at risk for OSA than those in the erosive esophagitis group.

Comparison of clinical and physiologic characteristics of NERD and erosive esophagitis is summarized in Table 10.2.

Patients presenting with GERD-related symptoms (heartburn and acid regurgitation) in the absence of alarm symptoms are likely to be treated empirically with an antireflux medication. Empiric PPI therapy is a reasonable approach to assess for GERD when it is suspected in patients with typical symptoms. However, this approach has a sensitivity of 78% and specificity of 54% and therefore has some limitations [94].

Barium esophagrams with double contrast can detect signs of esophagitis, although the overall sensitivity of this test is extremely low [95], and therefore it is not recommended as a diagnostic test in patients with NERD without dysphagia [96].

Diagnosis of NERD requires an upper endoscopy which is the most sensitive diagnostic tool for assessing GERD-related esophageal mucosal injury such as erosions, ulceration, stricture, Barrett’s esophagus, and others. A negative endoscopy may suggest the presence of NERD, although the sensitivity of diagnosing Los Angeles Grade A and even B has been relatively low, resulting in overdiagnosis of these lesions. Endoscopy has excellent specificity for erosive esophagitis when the LA classification is used [97]. All patients suspected to have NERD on upper endoscopy should undergo biopsies of the esophagus to assess for the presence of eosinophilic esophagitis (EoE) [98, 99]. Similarly, in GERD patients refractory to PPI therapy, EoE has been identified as a potential underlying mechanism in up to 8% of cases [100]. Therefore, esophageal biopsies to assess for EoE in patients with PPI refractory GERD-related symptoms are commonly performed [12].

Several studies have evaluated the usefulness of identifying dilated intercellular spaces (DIS) in the characterization of GERD and diagnosis of NERD [65, 101]. A recent study by Kundulski et al. aimed to differentiate NERD from functional heartburn by determining the presence or absence of DISs and other microscopic inflammatory changes in the distal esophagus [102]. Basal cell hyperplasia, DIS, and total inflammatory score (P < 0.05–0.001) provided the required distinction between the two disorders, with the highest discrimination factor being DIS. There were no significant histomorphological abnormalities of the esophageal mucosa in patients with functional heartburn and normal controls. DIS was also correlated with acid reflux parameters by means of acid exposure time, number of acid reflux episodes, as well as acid-gas reflux episodes. However, assessment of DIS requires an electron micrograph, a tool that is not routinely used by pathologists.

The role of esophageal biopsies to differentiate patients with normal endoscopy to those with NERD, reflux hypersensitivity, and functional heartburn remains controversial. It is still unclear at what level of the esophagus biopsies should be obtained.

Studies using high-resolution magnification endoscopy, chromoendoscopy (Lugol), and narrow band imaging (NBI) have demonstrated the presence of minimal mucosal changes at the squamocolumnar junction (SCJ) of NERD patients with otherwise normal-appearing mucosa by conventional upper endoscopy. These minimal changes include vascular injection or vascular spots above the Z-line, villous mucosal surface, microerosions, increased vascularity at the SCJ, and islands of columnar cell epithelium above the Z-line [103–106]. However, thus far there is still no consensus regarding the definition of “minimal changes” and what mucosal abnormalities fall under this category.

Kiesslich et al. evaluated several endoscopic minimal changes in healthy controls compared with NERD patients, before and after treatment with 20 mg esomeprazole using high-resolution magnification endoscopy [103]. Overall, more patients with NERD had punctate erythema above the Z-line that corresponded to blood vessels shining through the mucosa. Sharma et al. have demonstrated by using narrowband imaging that dilated and increased number of intrapapillary capillary loops were the most sensitive parameters for the diagnosis of NERD with minimal changes (sensitivity of 90% and a specificity of 70%) [107].

The clinical value of identifying SCJ “minimal changes,” using specialized endoscopy and other advanced visualization techniques, remains to be determined. By using pH monitoring as the gold standard, minimal changes were found to have a sensitivity for NERD that ranges from 60 to 90%, and a specificity that ranges from 64 to 83% [106].

The next step in diagnosing NERD after a negative upper endoscopy is to determine whether pathological gastroesophageal reflux is present using ambulatory reflux testing. In patients who are off treatment, a pH test should be performed. However, in patients who are on PPI treatment, there is no clear consensus whether reflux monitoring should be performed after stopping PPI therapy or while on medication [12, 108]. Overall, the approach is based on the patient’s clinical presentation and pretest probability of having GERD [108]. Patients with unproven GERD (i.e., no prior documented evidence of reflux-related pathology on endoscopy or ambulatory reflux monitoring) should be studied off PPI therapy (Fig. 10.2) [12]. In contrast, patients with proven history of GERD should be studied on PPI therapy (Fig. 10.1). Reflux monitoring off PPI can be performed with catheter-based or wireless pH capsule. Reflux monitoring on PPI (twice daily) should be performed with the impedance-pH technique to primarily evaluate for the presence of nonacid reflux. Diagnosis of NERD depends on the presence of abnormal esophageal acid exposure detected by either the catheter-based pH test or the wireless pH capsule [12]. However, an estimated 37–50% of patients with normal endoscopy have normal esophageal pH assessment off antireflux treatment [10]. In a recent study, Savarino et al. demonstrated that in patients with normal endoscopy undergoing impedance + pH testing, 40% had abnormal acid exposure (NERD), 36% showed symptom–reflux correlation in the absence of abnormal reflux parameters (reflux hypersensitivity), and 24% had normal pH–impedance monitoring without reflux-symptom association (functional heartburn) [48].

Esophageal manometry is of limited value in the primary diagnosis of NERD. It is recommended before consideration of antireflux surgery to rule out achalasia or scleroderma-like esophagus [108]. However, it should be considered in patients with NERD if there is any associated dysphagia. It is also commonly performed in patients with PPI-refractory GERD-related symptoms since certain motility disorders may have similar clinical presentation [109].

Baseline impedance levels have been suggested to help in distinguishing between NERD patients and those with functional heartburn. A recent study by Kandulski et al. demonstrated that baseline impedance was significantly lower in patients with erosive reflux disease or NERD than in those with functional heartburn (Fig. 10.4) [110]. By using baseline impedance, the authors observed a 78% sensitivity and 71% specificity in differentiating patients with erosive reflux disease or NERD from those with functional heartburn.

Recently, the measurement of esophageal mucosal impedance has been evaluated in the diagnosis of GERD. Mucosal impedance (MI) , a minimally invasive, simple, and low-cost device, can assess esophageal mucosal impedance during an upper endoscopy [111]. In a prospective longitudinal study, median MI values were significantly lower at the site of erosive mucosa than other nonerosive regions, and were significantly lower at 2 cm above the squamocolumnar junction in patients with GERD, as compared to those without GERD [111]. The researchers then evaluated the role of MI in patients with erosive esophagitis, NERD, achalasia, eosinophilic esophagitis, and non-GERD (dyspepsia symptoms without objective evidence of GERD) using a follow-up longitudinal study [112]. Findings were compared with those from wireless pH monitoring. MI values were found to be significantly lower in patients with GERD (erosive esophagitis or NERD) or eosinophilic esophagitis than in patients with reflux-related symptoms with nonerosive mucosa and normal pH or patients with achalasia. In addition, the recorded pattern of MI in patients with GERD differed from that in patients without GERD or those with eosinophilic esophagitis. These MI changes normalized with acid-suppressive therapy. The recorded MI patterns identified patients with erosive esophagitis with higher levels of specificity (95%) and positive predictive values (96%) than wireless pH monitoring (64% and 40%, respectively) [112].

The goals of treatment in NERD include acute and long-term relief of symptoms, prevention of symptom relapse, and improvement in quality of life. In general, therapeutic requirements for patients with NERD are similar to those for patients with erosive esophagitis. Proton pump inhibitors are the most efficacious therapeutic modality in NERD patients. In a meta-analysis, van Pinxteren et al. demonstrated that the relative risk for heartburn remission in placebo-controlled trials of patients with NERD was 0.68 (95% CI: 0.59–0.78) for PPIs versus placebo and 0.84 (95% CI: 0.74–0.95) for H2RA versus placebo [113]. The relative risk for PPIs versus H2RAs was 0.74 (95% CI: 0.53–1.03).

A number of studies evaluated the efficacy of PPIs in NERD patients. In a multicenter, randomized, double-blind study, omeprazole 20 mg once daily was compared with placebo in controlling symptoms of 209 patients with NERD [114]. After 4 weeks of therapy, 57% of patients in the omeprazole group were free of heartburn, 75% were free of acid regurgitation, and 43% were completely asymptomatic. In another study, 509 NERD patients were randomized to omeprazole 20 mg/day, omeprazole 10 mg/day, or placebo over 4 weeks [15]. The authors found that 46% of patients treated with omeprazole 20 mg/day, 31% treated with omeprazole 10 mg/day, and 13% of those who received placebo reported complete relief of heartburn. Another 4-week study included 203 patients with NERD who were randomized to either rabeprazole 20 mg once daily or placebo [115]. At the end of the study period, 56.7% of the patients receiving rabeprazole reported satisfactory symptom relief when compared with 32.2% of those receiving placebo. A study that utilized a wireless pH capsule has demonstrated that PPIs can normalize esophageal acid exposure in patients with NERD within 48 h after initial administration [116].

Katz et al. performed two randomized, double-blind, 4-week, multicenter trials with identical methodology comparing once-daily esomeprazole (40 mg or 20 mg) with placebo in patients with NERD [117]. Patients treated with either dose of esomeprazole were 2–3 times more likely to achieve complete resolution of heartburn when compared to patients treated with placebo. The percentage of heartburn-free days was significantly higher with esomeprazole 40 or 20 mg than with placebo in each of the studies. In a 4-week, double-blind, placebo-controlled study that included 947 patients with NERD, dexlansoprazole 30 and 60 mg/day was shown to be superior to placebo in providing 24-h heartburn-free days and nights (54.9% vs. 17.5% and 80.8% vs. 51.7%, respectively) [118]. In a systematic review, indirect comparisons revealed significant difference in heartburn control of patients with NERD treated with either esomeprazole or dexlansoprazole at 4 weeks. Dexlansoprazole 30 mg was shown to be more effective than esomeprazole 20 or 40 mg (RR: 2.01, 95% CI: 1.15–3.51; RR: 2.17, 95% CI: 1.39–3.38) [119].

It has been recently proposed that the goal of achieving a complete symptom control in NERD patients is unrealistic. Unlike erosive esophagitis patients, those with NERD rarely report complete symptom resolution on PPI treatment regardless of the dose. It also appears that NERD patients are content with certain level of residual symptoms. Thus, physicians should accurately present to NERD patients the clinical goal of symptom improvement rather than complete symptom resolution [120].

Since NERD, in general, is not thought to be a progressive disorder, treatment for many patients could be symptom driven. The use of an on-demand (patient initiates PPI treatment and consumes for the duration they desire) or intermittent (patient initiates PPI treatment, but takes it for a fixed period of time) PPI therapy is more convenient and cost effective, relieves GERD-related symptoms, reduces the likelihood of acid rebound, and improves quality of life [121–126]. In addition, Nagahara et al. conducted an open-label study in Japan comparing the efficacy of continuous versus on-demand treatment with omeprazole 20 mg for 6 months. The authors demonstrated comparable efficacy between the two groups [127]. Thus, on-demand or intermittent therapy with a PPI is an attractive therapeutic strategy for NERD patients in clinical practice.

There is paucity of data regarding risk factors for PPI refractoriness in NERD patients. A recent study conducted by Shi et al. aimed to determine which factors may potentially predict PPI treatment results in 117 patients with NERD. It was demonstrated that NERD patients who failed PPI treatment had lower BMI and more commonly concomitant functional dyspepsia symptoms [128]. PPI failure patients had a higher percentage of type I esophagogastric junction (EGJ) morphology, increased EGJ augmentation, higher prevalence of esophageal motility disorders, and a higher rate of negative symptom index. Concomitant functional dyspepsia symptoms, EGJ augmentation, and negative SI were independent risk factors for PPI failure in NERD.

The proportion of NERD patients responding to a standard dose of PPI is approximately 20–30% lower than what has been documented in patients with erosive esophagitis. In a systematic review, the pooled PPI symptomatic response rate was 37% (95% CI: 34.1–39.3) in NERD patients and 56% (95% CI: 51.5–59.5) in those with erosive esophagitis [129]. Therapeutic gain was 27.5% in NERD as compared with 48.9% in erosive esophagitis (Fig. 10.5). Furthermore, patients with NERD demonstrate a close relationship between response to PPI therapy and degree of esophageal acid exposure. The greater the distal esophageal acid exposure, the higher the proportion of NERD patients reporting symptom resolution [15]. This is the opposite of what has been observed in patients with erosive esophagitis, where increased esophageal inflammation and thus acid exposure have been associated with lower response rate to PPI once daily. Patients with NERD also demonstrate longer lag time to sustained symptom response when compared to patients with erosive esophagitis (two- to threefold). In addition, patients with NERD demonstrate similar symptomatic response to half and full standard dose of PPI [130], unlike patients with erosive esophagitis who demonstrate an incremental increase in healing and symptom resolution (dose–response effect). The differences in therapeutic response parameters between NERD and erosive esophagitis are attributed to the heterogeneity of the NERD group. In some early therapeutic trials, patients with functional heartburn were not actively excluded. However, even after excluding functional heartburn patients, the symptomatic response rate of NERD patients to PPI remains lower than what has been observed in erosive esophagitis patients. This is likely due to the fact that most NERD patients demonstrate only modest abnormal esophageal acid exposure. In addition, esophageal hypersensitivity is an important underlying mechanism in symptom generation of NERD patients.

There is limited data on the treatment of NERD patients refractory to PPI treatment. NERD patients compose the largest group of patients who failed standard-dose PPI treatment. Failure of double-dose PPI reflects more the presence of functional heartburn or reflux hypersensitivity.

Compliance, adherence, and lifestyle modifications should be considered first-line management for all patients with NERD refractory to antireflux therapy. Poor compliance and adherence to PPI treatment are common among all GERD patients. Several factors may contribute to patient compliance. These factors include knowledge about the treated disorder and the prescribed drug, perceived severity of symptoms, side effects, number of pills or additional medications, and patient’s age and personality [131]. Studies have demonstrated a rapid decline in compliance from the time the antireflux medication was first prescribed and further declines with increase in dosing [132]. Moreover, poor adherence with timing of PPI consumption is rampant among both GERD and NERD patients. Gunaratnam et al. demonstrated that of the 100 patients with persistent GERD symptoms while on PPI treatment, only 46% were dosing optimally [133]. Of those who dosed suboptimally, 38.9% consumed their PPI >60 min before a meal, 29.6% after a meal, and 27.8% at bedtime. Patients should also be educated on lifestyle modifications. Heavy meals, exercise, increased alcohol consumption, and other daily activities might lead to or exacerbate symptoms in patients with NERD [134]. Consequently, it is important to recommend avoidance of specific lifestyle activities that have been identified by patients or physicians as triggering GERD-related symptoms [1]. In addition, weight loss, elevation of the head of the bed, and avoiding food consumption at least 3 h before bedtime have been shown to improve symptoms in GERD patients [135].