Achalasia is a serious motility disorder of the esophagus that impacts more than 5,000 people in the US each year. Patients with achalasia experience damage to muscle and nerve cells in the esophagus, resulting in a loss of the peristaltic activity that normally pushes food through the esophagus into the stomach, and failure of the lower esophageal sphincter (LES) to relax with swallowing, which further blocks the transit of food. Thus, achalasia patients experience severe swallowing difficulty that adversely impacts their quality of life. Because the etiology of achalasia is not known, current therapies do not cure the disease and only address its symptoms. Exciting new research from Baylor Scott & White Research Institute (BSWRI) shows that LES muscle in achalasia exhibits profound mast cell degranulation, a hallmark of allergy-induced inflammation. This work adds support to the novel hypothesis developed by BSWRI researchers that achalasia might be an allergic disorder.  

In 2018, Stuart Spechler, MD, Vani Konda, MD, and Rhonda Souza, MD, physician-researchers at the Center for Esophageal Research at BSWRI and authors on the new study, hypothesized in the American Journal of Gastroenterology that reports of eosinophils in the LES muscle of achalasia patients, as well as the success of steroid therapies for some achalasia patients, could be evidence of an allergy-related etiology. This is a difficult hypothesis to study because of challenges with accessing samples of achalasia LES muscle, which requires an invasive procedure, and a lack of high-quality control muscle tissue for comparison.

For their latest study, published in Neurogastroenterology & Motility in December 2020, surgical members of the Center for Esophageal Research at BSWRI (Eitan Podgaetz, MD, Marc Ward, MD, and Steven Leeds, MD) obtained LES samples from patients undergoing Heller myotomy procedures for the treatment of achalasia at Baylor University Medical Center at Dallas, part of Baylor Scott & White Health. Heller myotomy is a laparoscopic procedure wherein the LES muscle is cut to prevent it from obstructing the passage of food and liquids into the stomach. Since the LES is cut intentionally, the procurement of biopsy samples for research adds essentially no risk to the procedure.  Unlike prior studies, which have typically used no controls or control samples derived from patients with cancer of the esophagus, this study used healthy LES samples from heart-beating, deceased organ donors as controls. This resource of tissue samples for research allowed the team to answer questions that were not previously possible to address.

The researchers observed that mast cells were plentiful in the LES muscle from achalasia patients and controls. However, the researchers found intriguing evidence of profound mast cell degranulation in the patient-derived LES muscle, but not in LES muscle of control subjects. Mast cell degranulation, which is characteristic of IgE-mediated allergic disease, causes inflammatory agents and toxins to be released from mast cells into the surrounding tissue. These mast cell-derived substances have the potential to cause the muscle dysfunction and nerve damage that characterizes achalasia.  These findings support the researchers’ hypothesis that allergy can be an important cause of achalasia. Further evaluation of the LES muscle using RNA expression profiling of genes associated with intracellular calcium handling and muscle contraction grouped patients into 2 “mototype” clusters that distinguished patients with the different types of achalasia identified by esophageal motility studies. These results led the researchers to propose the intriguing hypothesis that the patient’s LES mototype might influence the response to mast cell degranulation, resulting in the achalasia disease subtypes. If further studies can establish that allergy-induced mast cell degranulation in esophageal muscle causes achalasia, this will lead to novel, non-invasive medical treatments that can restore normal esophageal function and thereby alleviate the substantial impact of this presently incurable disease on quality of life, health-care cost burden, and work productivity.

This study was funded entirely by BSWRI as part of the Baylor Scott & White commitment to accelerating translational research. The Center for Esophageal Research at BSWRI is committed to combining groundbreaking translational research on disorders of the esophagus and excellence in clinical care.

Melissa Nelson, post doc and first year GI fellow at Baylor Scott & White discussed the findings of this work for the American Neurogastroenterology Motility Society‘s YouTube channel. Watch her full interview.