What is the mechanism of action (MOA) of achalasia?

Mechanism of Action of Achalasia

Achalasia is primarily caused by autoimmune-mediated destruction of the myenteric plexus neurons in the esophagus, leading to impaired lower esophageal sphincter (LES) relaxation and absent peristalsis in the esophageal body. 1

Pathophysiological Mechanisms

Primary Pathology

• The fundamental pathophysiological mechanism involves the destruction of inhibitory neurons in the myenteric plexus of the esophagus 1, 2
• This neuronal loss particularly affects inhibitory neurons that use nitric oxide and vasoactive intestinal peptide as neurotransmitters
• The resulting imbalance between excitatory and inhibitory innervation leads to:
  • Failure of LES relaxation during swallowing
  • Loss of coordinated peristalsis in the esophageal body

Autoimmune Etiology

• Strong evidence supports an autoimmune component in the pathogenesis 1
• The disease involves cell-mediated and possibly antibody-mediated mechanisms targeting esophageal myenteric nerves 2
• This autoimmune attack results in progressive aganglionosis of the esophageal myenteric plexus 3

Potential Triggers

Several factors have been implicated in triggering the autoimmune process:

1. Viral infections:

   • Certain viruses may initiate the autoimmune response in genetically susceptible individuals 1
   • SARS-CoV-2 has been specifically implicated as a potential trigger through immune cross-reactivity 1

2. Chagas Disease:

   • Infection with Trypanosoma cruzi can trigger achalasia-like symptoms through inflammatory mechanisms 1
   • Relevant in patients with travel history to Central/South America

3. Paraneoplastic manifestation:

   • Can occur as a paraneoplastic syndrome in certain malignancies
   • Most commonly associated with lymphoma, lung cancer, and breast cancer 1

4. Genetic susceptibility:

   • Certain genetic factors may predispose individuals to develop achalasia when exposed to environmental triggers 1

Clinical Manifestations and Classification

The pathophysiological changes result in three distinct subtypes based on high-resolution manometry findings:

1. Type I (Classic Achalasia):

   • Negligible pressurization within the esophagus 3
   • Complete absence of peristalsis

2. Type II Achalasia:

   • Most common presenting subtype 3, 1
   • Features panesophageal pressurization with uniform simultaneous pressurization bands spanning from the upper to lower sphincter 3
   • Generally has the best response to therapy 1

3. Type III (Spastic) Achalasia:

   • Characterized by premature (spastic) contractions
   • Latency between upper sphincter relaxation and arrival of rapidly propagated contraction at distal esophagus is <4.5 seconds 3
   • Poorest response to all treatments 1

Disease Evolution

• Achalasia evolves over a variable timespan, with progressive neuronal loss 3
• Early in the disease, inhibitory innervation may be partially preserved
• Late in the disease, both LES pressure and integrated relaxation pressure (IRP) might become very low 3
• The progressive nature explains why diagnosis can be challenging in early or incompletely evolved disease

Associated Conditions

Achalasia shows strong associations with several autoimmune conditions:

• Systemic sclerosis
• Addison's disease
• Other autoimmune disorders 1

Understanding the mechanism of action of achalasia is crucial for appropriate diagnosis and treatment selection, particularly when considering the different therapeutic approaches for the various subtypes of the disease.