Pathophysiology of Achalasia

Background: Achalasia is a rare primary esophageal motility disorder of the esophageal smooth muscle, characterized by abnormal relaxation of the lower esophageal sphincter and associated with abnormal, spastic, or absent esophageal body peristalsis. Summary: The primary pathophysiological defect is abnormal esophageal inhibitory nerve function from neuronal death in the esophageal neuronal plexuses and ganglia that control esophageal smooth muscle peristalsis. This is a consequence of an autoimmune cytotoxic insult from molecular mimicry following an intercurrent viral infection, typically herpes simplex virus, varicella zoster virus, human papillomavirus, measles virus, and even the COVID-19 virus. Neuronal inflammation rather than death can lead to an imbalance between excitatory and inhibitory forces, and varying degrees of retained spastic, premature or even normal peristalsis in the smooth muscle esophageal body. Chagas disease caused by Trypanosoma cruzi, eosinophilic inflammation, direct infiltration with neoplastic cells from adjacent cancers, or humoral autoimmune destruction from distant cancers can also result in an achalasia-like syndrome. Mechanical obstruction from tight strictures, anti-reflux or bariatric surgery, and extrinsic compression can mimic the manometric features of achalasia. Chronic opioid medication usage can result in a clinical and pathophysiological syndrome identical to spastic achalasia. Key Messages: Careful clinical evaluation and judicious interpretation of esophageal function tests following pathophysiological principles can lead to an accurate diagnosis of achalasia, opening the door to durable permanent disruption of the malfunctioning esophageal smooth muscle and resulting in symptom relief.