GERD—diagnosis

The endoscopic diagnosis and treatment of GERD will change dramatically in coming years. Current endoscopic assessment of reflux is binary; patients either have nonerosive reflux disease, in which case the diagnosis cannot be confirmed endoscopically, or there is grossly evident erosive disease that is diagnostic, however, relatively uncommon. In the future, however, very precise endoscopic assessments of GE reflux will be developed; in particular one will be able to measure and assess early disruption and increased spacing of esophageal epithelial intracellular tight junctions, which is considered to be the earliest histologic sign of GERD. Using confocal endoscopic imaging, assessment of intracellular spacing can be determined with a high degree of reproducibility and corresponds to microscopic histologic samples. With this technology, patients with grossly nonerosive esophageal mucosal findings can be subcategorized into those with early cellular changes consistent with GE reflux, versus those with no confocal microscopic changes.

Using this technology in conjunction with pH profiles, one also could determine response to therapy. It would be highly unlikely that patients with restored normal epithelial intracellular spacing would continue to have symptomatic heartburn. Thus patients with ongoing reflux symptoms, and those with functional complaints, should be readily discernible. Antiacid medication also would be titratable to intracellular spacing, and one should be readily able to determine nonerosive GERD patients with true failed medical management.

Another coming advance in the realm of GERD diagnostics is the endoscopic functional luminal imaging procedure or Endo-FLIP (Crospon Diagnostics, Galway, Ireland). The FLIP technology involves placing a deflated volume-based Barostat bag through the biopsy channel of the endoscope, positioning the Barostat bag across the GE junction, and slowly inflating it with water to obtain a high-fidelity measurement of the cross-sectional diameter of this region. As the Barostat bag is filled with water, pressure sensors within the bag construct a three-dimensional image of the GE junction and lower esophageal sphincter (LES). The determined cross-sectional diameter and distensibility of the esophagus in the region of the GE junction is an accurate indicator of lateral displacement of the diaphragmatic crus, and it indirectly measures LES compliance in this area and GE yield pressure. It has become clear in recent years that measurement of the LES pressure (ie, squeeze pressure) is not particularly valuable in predicting GERD, because most GERD patients actually have normal LES pressures.

The FLIP procedure can assess the more important LES compliance or gastric yield (ie, the ability of the GE junction to resist opening from elevated gastric volumes and pressures as patients fill their stomachs with food or air). The compliance of this area or the pressure at which the GE junction yields to increased gastric volumes is likely to be a much more accurate predictor of GERD and is the functional equivalent of the endoscopic Hill grade anatomy assessment. This technique also helps determine lateral displacement of the diaphragmatic crus, which is a key, but previously immeasurable, component of GE reflux. Current endoscopic practice can assess only axial displacement of the GE junction proximal to the diaphragm (ie, a sliding hiatal hernia); however, this is a highly variable and inaccurate measure, particularly as regards reducible, sliding hiatal hernias.

GERD—new therapeutic options

Regarding future endoscopic therapy for GERD, there are several exciting developments to anticipate. One potential development is the option of stem cell injection directly into the area of the LES, with biologic regrowth of LES cells and restoration of sphincter dynamics. In recent years, it has become possible to extract human somatic cells and via bacteriophage viral genomic or drug manipulation, convert ordinary somatic cells into inducible pluripotent stem cells. When these inducible pluripotent stem cells are injected into target LES tissue with the proper milieu characteristics, the stem cells can regenerate into LES sphincter cells and restore normal sphincter squeeze characteristics. Success of this technology, however, likely will depend on other reflux parameters including a patient’s anatomy, axial displacement of the native LES, lateral displacement of the diaphragmatic crus, and whether the native LES was normal or hypotensive to begin with.

Endoscopic, endoluminal antireflux devices have failed in the past, including

• 
  

  Various sewing and plicating devices (BARD endocinch, Murray Hill, New Jersey; HizWhiz; NDO plicator, Mansfield, Massachusetts)

  
  
• 
  

  Radiofrequency devices intended to tighten the LES (Stretta, Curon Inc, Fremont, California)

  
  
• 
  

  Injectable devices that either tried to impact sphincter compliance (Enteryx) or narrow the lumen in the region of the LES to create resistance to retrograde flow (Gatekeeper, Medtronic Inc, Fridley, Minnesota)

There are new developments in this area, however. Durasphere (Carbon Medical Technologies, Maple Grove, Minnesota) is a new injectable bulking agent composed of micronized carbon spheres that are injected in the region of the GE junction. A recent pilot publication has demonstrated feasibility of this agent for treating GERD and has shown that the microcarbon spheres are safe, durable, effective and nonmigratory. In this small study, 70% of patients with mild-to-moderate GERD were able to discontinue all reflux medications at 12 months, and 40% normalized their pH scores. Moreover, the technique is simple and caused no postprocedure pain or dysphagia. Another new device (Esophyx, Endogastric Solutions Inc, Redmond, Washington) tries to create an endoscopic Nissen fundoplication in an endoluminal fashion, although results to date have been suboptimal.

The LINX device (Torax Medical Incorporated, Shoreview, Minnesota) is a beaded magnetic bracelet that is placed around the esophagus in the region of the LES. The individual magnetic beads spread apart to allow food to pass, and to provide for belching and vomiting, but then re-attract to restore compliance and yield pressure dynamics at the GE junction. Extensive animal testing and early human clinical data with some patients followed out to 3 years have shown this device to be very safe with no reported migration or erosion to date. The device does not appear to affect resting LES tone; rather it appears to prevent inappropriate LES opening. Early clinical data appear impressive for this device; in a recent study of 44 implanted GERD patients, 80% achieved a normal acid pH score at 1 year, and 90% completely eliminated the need for any antiacid medication. GERD health-related quality of life scores improved from initial values of 26.5 to 1 year scores of 3.0. The LINX device is placed laparoscopically, and is technically simpler and quicker than performing a Nissen fundoplication. The procedure is being performed on an outpatient basis, and patients can resume standard diets later that day. There is also the possibility for endoscopic placement of the device via a natural orifice transluminal endoscopic approach (NOTES). The device has significant potential in obviating the need for Nissen fundoplication in many severe GERD patients, and it can extend device therapy to the many reflux patients dissatisfied with medical management but not willing to undergo the physiologic disruption of a Nissen procedure.

Given the previous discussion, it is clear that the current practice of GERD will change dramatically in the future. Current practice involves maintaining virtually all GERD patients on proton pump inhibitor therapy, recognizing that a significant percentage of patients will remain dissatisfied, with referral of only a select few severe GERD patients to Nissen surgery. In the future, given some of the just described new diagnostic entities, one will be able to

• 
  

  better and more accurately subcategorize GERD patients into those most amenable to medical, endoscopic, or surgical management

  
  
• 
  

  choose the most appropriate therapy for an individual patient based on LES pressure, length, compliance and yield pressure, microscopic intracellular dynamics, lateral displacement of the diaphragmatic crus, axial displacement of the GE junction, and pH characteristics.

The range of therapeutic options also will increase, giving practitioners the ability to tailor specific therapies to specific physiologic deficits, resulting in better outcomes.

GERD—new therapeutic options

Regarding future endoscopic therapy for GERD, there are several exciting developments to anticipate. One potential development is the option of stem cell injection directly into the area of the LES, with biologic regrowth of LES cells and restoration of sphincter dynamics. In recent years, it has become possible to extract human somatic cells and via bacteriophage viral genomic or drug manipulation, convert ordinary somatic cells into inducible pluripotent stem cells. When these inducible pluripotent stem cells are injected into target LES tissue with the proper milieu characteristics, the stem cells can regenerate into LES sphincter cells and restore normal sphincter squeeze characteristics. Success of this technology, however, likely will depend on other reflux parameters including a patient’s anatomy, axial displacement of the native LES, lateral displacement of the diaphragmatic crus, and whether the native LES was normal or hypotensive to begin with.

Endoscopic, endoluminal antireflux devices have failed in the past, including

• 
  

  Various sewing and plicating devices (BARD endocinch, Murray Hill, New Jersey; HizWhiz; NDO plicator, Mansfield, Massachusetts)

  
  
• 
  

  Radiofrequency devices intended to tighten the LES (Stretta, Curon Inc, Fremont, California)

  
  
• 
  

  Injectable devices that either tried to impact sphincter compliance (Enteryx) or narrow the lumen in the region of the LES to create resistance to retrograde flow (Gatekeeper, Medtronic Inc, Fridley, Minnesota)

There are new developments in this area, however. Durasphere (Carbon Medical Technologies, Maple Grove, Minnesota) is a new injectable bulking agent composed of micronized carbon spheres that are injected in the region of the GE junction. A recent pilot publication has demonstrated feasibility of this agent for treating GERD and has shown that the microcarbon spheres are safe, durable, effective and nonmigratory. In this small study, 70% of patients with mild-to-moderate GERD were able to discontinue all reflux medications at 12 months, and 40% normalized their pH scores. Moreover, the technique is simple and caused no postprocedure pain or dysphagia. Another new device (Esophyx, Endogastric Solutions Inc, Redmond, Washington) tries to create an endoscopic Nissen fundoplication in an endoluminal fashion, although results to date have been suboptimal.

The LINX device (Torax Medical Incorporated, Shoreview, Minnesota) is a beaded magnetic bracelet that is placed around the esophagus in the region of the LES. The individual magnetic beads spread apart to allow food to pass, and to provide for belching and vomiting, but then re-attract to restore compliance and yield pressure dynamics at the GE junction. Extensive animal testing and early human clinical data with some patients followed out to 3 years have shown this device to be very safe with no reported migration or erosion to date. The device does not appear to affect resting LES tone; rather it appears to prevent inappropriate LES opening. Early clinical data appear impressive for this device; in a recent study of 44 implanted GERD patients, 80% achieved a normal acid pH score at 1 year, and 90% completely eliminated the need for any antiacid medication. GERD health-related quality of life scores improved from initial values of 26.5 to 1 year scores of 3.0. The LINX device is placed laparoscopically, and is technically simpler and quicker than performing a Nissen fundoplication. The procedure is being performed on an outpatient basis, and patients can resume standard diets later that day. There is also the possibility for endoscopic placement of the device via a natural orifice transluminal endoscopic approach (NOTES). The device has significant potential in obviating the need for Nissen fundoplication in many severe GERD patients, and it can extend device therapy to the many reflux patients dissatisfied with medical management but not willing to undergo the physiologic disruption of a Nissen procedure.

Given the previous discussion, it is clear that the current practice of GERD will change dramatically in the future. Current practice involves maintaining virtually all GERD patients on proton pump inhibitor therapy, recognizing that a significant percentage of patients will remain dissatisfied, with referral of only a select few severe GERD patients to Nissen surgery. In the future, given some of the just described new diagnostic entities, one will be able to

• 
  

  better and more accurately subcategorize GERD patients into those most amenable to medical, endoscopic, or surgical management

  
  
• 
  

  choose the most appropriate therapy for an individual patient based on LES pressure, length, compliance and yield pressure, microscopic intracellular dynamics, lateral displacement of the diaphragmatic crus, axial displacement of the GE junction, and pH characteristics.

The range of therapeutic options also will increase, giving practitioners the ability to tailor specific therapies to specific physiologic deficits, resulting in better outcomes.

Eosinophilic esophagitis

Current endoscopic practice for diagnosing eosinophilic esophagitis involves visual inspection, searching for mucosal edema, multiple rings or mucosal furrowing, and evidence of luminal narrowing or stricture formation. Random endoscopic biopsies also are obtained looking for eosinophilic infiltration in the esophageal mucosa. Unfortunately, current endoscopic diagnosis of eosinophilic esophagitis is problematic, however, because of the fact that approximately 30% of patients with eosinophilic esophagitis have normal-appearing mucosa. Additionally, the disease is often patchy, requiring numerous random biopsies over several regions of the esophagus. Moreover, the exact density of eosinophils per high-powered field has not been established for accurate diagnosis. A count of 15 intraepithelial eosinophils per high-powered field is considered to be the absolute minimum number to make a diagnosis in the context of accompanying symptoms and endoscopic findings, but the methods for enumerating eosinophils is highly variable, and there is not consensus on this issue. Furthermore, using this minimum number, a single biopsy specimen only has an approximate 55% sensitivity in the diagnosis of eosinophilic esophagitis, whereas five or more specimens have a sensitivity approaching 100%. Treatment of this disease is also problematic. Elimination diets often are recommended under the supervision of a registered dietitian, but even when this approach is successful, it is unclear which food group is actually responsible for the eosinophilic infiltration, and it is difficult to determine which food groups can be reintroduced with safety. Topical or systemic corticosteroids also may be used, with oral fluticasone as the preferred agent; however, in a recent double-blind, placebo-controlled trial, only 50% of patients with eosinophilic esophagitis responded to this therapy.

It would be ideal to have an endoscopic technology that could readily and more accurately measure and grade eosinophilic infiltration of the esophagus compared with biopsy and histology, and rapidly assess response to specific food group avoidances. In the future, rather than assess gross endoscopic visual findings and histology, practitioners may be using technology similar to Endo-FLIP to rapidly and accurately determine esophageal wall compliance. Esophageal wall compliance should correlate to the degree of eosinophilic infiltration, and practitioners may be able to more accurately characterize the degree of disease via serial compliance measurements in the body of the esophagus. Future patients with presumed eosinophilic esophagitis could have a baseline FLIP measurement obtained, confirming the diagnosis. Patients then would be entered into an elimination diet protocol, with a repeat FLIP examination used to document improvement. The reintroduction of specific foods with serial compliance measurements then could determine rapidly which specific food group needs to be avoided. This new way of measuring and assessing esophageal wall compliance could obviate the need for steroid use and might eliminate discrepancies based on random biopsy and interobserver disagreement of density of histologic eosinophilic infiltration.