New insights into the pathophysiology of achalasia and implications for future treatment

Abstract

Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter (LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient’s quality of life.

Mechanical dilation, botulinum toxin A injection, and surgical myotomy with fundoplication for treatment of lower esophageal sphincter achalasia‐like syndrome in dogs

“…In humans, esophageal motility disorders are better classified allowing for identification of patients with conditions that may benefit from targeted intervention . Achalasia, a primary esophageal motility disorder in people, results from a selective loss of inhibitory myenteric neurons leading to a failure of the LES to relax in response to pharyngeal swallowing and impaired esophageal peristalsis . It represents a rare cause of ME that responds to targeted intervention and is considered distinct from conditions that cause esophageal hypomotility without functional LES obstruction.…”

“…7 Achalasia, a primary esophageal motility disorder in people, results from a selective loss of inhibitory myenteric neurons leading to a failure of the LES to relax in response to pharyngeal swallowing and impaired esophageal peristalsis. 24 It represents a rare cause of ME that responds to targeted intervention and is considered distinct from conditions that cause esophageal hypomotility without functional LES obstruction. This condition has been suspected in dogs, with a few case reports over the last 4 decades and most presumptive diagnoses being made without manometry or dynamic imaging studies.…”

Infectious agents as potential triggers for autoimmunity in achalasia

“…However, when HSV-1 is reactivated, IFN-γ and IL-2 production is increased, and infected neurons are lysed 17 . Thus, latency and active replication of HSV-1, but not cytomegalovirus or Epstein-Barr virus, has been detected along the myenteric plexus of achalasia patients 10,18,19 . Our group 12 ( Fig.…”

Triosephosphate isomerase, carbonic anhydrase, and creatinine kinase‐brain isoform are possible antigen targets in patients with achalasia

“…The pathophysiological mechanism of achalasia remains unknown. However, several studies suggest that it involves an interaction between inflammatory and autoimmune responses, such as viral infections, in genetically susceptible individuals . The proposed pathogens in triggering the inflammatory response in achalasia, include herpes simplex virus (HSV), varicella‐zoster, measles, and human papillomavirus .…”