CLINICAL TRIALS REVIEW

The Esophagus: New Methodologies and Discoveries Lead to an

Evolution in Clinical PracticePeter J. Kahrilas, MD

AddressNorthwestern University Medical School, Division of Gastroenterology and Hepatology, Department of Medicine, Passavant Pavilion, Suite 746, 303 East Superior Street, Chicago, IL 60611-3053, USA.

Current Gastroenterology Reports 1999, 1:184–185Current Science Inc. ISSN 1522-8037Copyright © 1999 by Current Science Inc.

New understandings of disease management oftenevolve from new discoveries or the development of newmethodologies for investigation. This phenomenon isobserved several times in the reviews featured in thisissue. New tools in the investigation of esophageal physi-ology and in the treatment of esophageal disorders haveled us to reappraise our understanding of this enigmati-cally complex organ.

Illustrative of the above observation is the identificationof nitric oxide as the primary inhibitory neurotransmitter ofthe gastrointestinal tract. As detailed in the review by Dr.Ikuo Hirano, the previously mysterious culprit in the patho-genesis of achalasia, the nonadrenergic, noncholinergicinhibitory neurons of the myenteric plexus, have now beenidentified as nitric-oxide–containing neurons. These neu-rons are seemingly absent in achalasia patients, and theexperimental inhibition of nitric oxide in the normal esoph-agus induces functional compromise mimicking achalasia.Of course, the ultimate cause of this rare but important con-dition still remains elusive. However, hints of its autoim-mune origin can be found with the secondary disordersincluding Allgrove’s syndrome, autoimmune polyglandularsyndrome, and multiple endocrine neoplasia 2B.

Further impact of the discovery of nitric oxide as theprimary inhibitory neurotransmitter is found in the reviewof the mechanism of esophageal peristalsis in this issue byDr. Hyojin Park and Dr. Jeffrey Conklin. The esophagus is acurious organ, involving the transition from striated tosmooth muscle and from direct cholinergic neural controlto indirect neural control mediated through the excitatoryand inhibitory neurons of the myenteric plexus. Within thestriated muscle segment the sequential activation of the cir-cular muscle has long been appreciated to be attributableto central programming, with the consequent sequential

activation of cholinergic motor neurons. However, withinthe smooth muscle esophagus, the timing function resideswithin the myenteric plexus. This placement is evidencedby the observation that although the entire segment issimultaneously stimulated by the vagus, sequential con-traction still occurs. Seminal work by Dr. James Chris-tensen suggests that this timing function was accomplishedby a shifting of the dominance of the myenteric neuronsfrom excitatory in the proximal regions to inhibitory in thedistal regions; the timing of activation at a given locuswould thus be a function of the balance between theseinfluences. Colleagues of Dr. Christensen, Dr. Park and Dr.Conklin review our current concept of the physiology ofesophageal peristalsis along with the ultimate proof of thishypothesis using nitric oxide antagonists to reversibly dis-able the timing mechanism.

Perhaps no innovation has had greater impact on themanagement of esophageal disorders than the introduc-tion of the proton pump inhibitors. Just as the H2 receptorantagonists revolutionized the management of peptic ulcerdisease, the proton pump inhibitors have not only revolu-tionized the treatment of esophagitis but have also vastlyenhanced our understanding of gastroesophageal refluxdisease (GERD). In particular, patients with GERD areknown to experience a wide spectrum of symptoms, rang-ing from commonly experienced heartburn and acid regur-gitation to chest pain and extraesophageal symptoms.Furthermore, different individuals may experience differ-ent symptoms from what are essentially identical mechani-cal or chemical stimuli, and there is wide variation in therelationship between symptoms and objective esophagealabnormalities. In some instances, symptoms correlate wellwith objective esophageal findings, as in the patient whopresents complaining of painful reflux episodes and isfound to have severe esophagitis by endoscopy. In otherinstances, including some patients with Barrett’s esopha-gus or esophageal strictures, there is minimal symptoma-tology in the face of relatively severe endoscopic,radiologic, or manometric findings. Still other patientsmay experience symptoms despite normal esophagealstructural and functional tests. The reason for this widevariation in symptom perception is unclear; mechanisms

The Esophagus: New Methodologies and Discoveries Lead to an Evolution in Clinical Practice • Kahrilas 185

and pathways responsible for symptom perception in theesophagus remain largely unknown. Hypothetical explana-tions include differences in the sensitivity of the esoph-ageal mucosa, of the entire esophageal wall, or of centralnervous system processing of the afferent signal. The articleby Dr. Guoxiang Shi and colleagues in this issue reviewssome clinical observations of esophageal sensitivity andsymptom perception in GERD patients.

Another indirect result of the widespread usage of theproton pump inhibitors is an evolution in our understand-ing of Barrett’s metaplasia. Although the augmented acidsuppression attributable to the proton pump inhibitorsdoes not reverse Barrett’s metaplasia, their use in associa-tion with endoscopic biopsies was observed to result in theformation of squamous islands (or icebergs) within thearea of metaplasia. As reviewed by Dr. Brian Fennerty inthis issue, this observation led to experimentation with ahost of methods for ablative therapy including cautery,laser, and, most recently, photodynamic therapy. Althoughthis field is still in its infancy, it has been met with enor-mous interest in the face of the rapidly increasing inci-dence of adenocarcinoma of the esophagus amongWestern populations.

Yet another technological advance with a great impacton the management of esophageal disorders is the applica-tion of minimally invasive surgery. As described in thesepages by Drs. Thomas Eubanks and Carlos Pellegrini,patients with GERD, paraesophageal hernias, and achala-sia are now routinely operated on laparoscopically.Although controlled data comparing laparoscopic meth-ods to the alternative medical management is scarce, thereduced morbidity associated with laparoscopic surgeryhas dramatically increased patient acceptance. Clearly, thechoice between medical and surgical management of acha-lasia and GERD will be the focus of increasing scrutiny inthe years ahead.

Finally, I hope that the reader appreciates the labors ofthis group of distinguished authors. Each of them is emi-nent in the field, and they call upon not only the publishedliterature but also extensive clinical or investigational expe-rience. Our understanding of the esophagus has evolvedsubstantially in a relatively short period of time, and theseauthors have synthesized an enormous amount of infor-mation into a series of concise and thoughtful reviews. As apersonal note, I wish to thank each one of them for theirsuperb efforts.