What is the etiology of achalasia?

Etiology of Achalasia

Achalasia is primarily caused by autoimmune-mediated destruction of the myenteric plexus neurons in the esophagus, with multiple potential triggers including viral infections, particularly in genetically susceptible individuals. 1

Pathophysiological Mechanisms

Achalasia is characterized by two key physiological abnormalities:

• Loss of esophageal peristalsis
• Impaired relaxation of the lower esophageal sphincter (LES)

These abnormalities result from progressive degeneration of inhibitory neurons in the myenteric plexus, particularly those that release nitric oxide and vasoactive intestinal peptide, which are essential for LES relaxation and coordinated peristalsis.

Autoimmune Mechanisms

Evidence strongly supports an autoimmune component in achalasia pathogenesis:

• A German case-control study of 1,141 achalasia patients found significant association with autoimmune conditions (OR 1.49; 95% CI 1.23-1.80) 1
• Strongest associations were observed with systemic sclerosis and Addison's disease 1
• Inflammation of the myenteric plexus leads to aganglionosis 1

Infectious Triggers

Several infectious agents have been implicated:

1. Chagas Disease:

   • Trypanosoma cruzi causes esophageal dysfunction through immune cross-reactivity between the parasite's flagellar antigen and myenteric plexus 1
   • Gastrointestinal manifestations occur in 10-15% of chronically infected individuals 1
   • Affects approximately 300,000 individuals in the United States 1

2. Viral Infections:

   • SARS-CoV-2: Recent evidence shows acute-onset achalasia following COVID-19 infection 1
   • Mechanism: SARS-CoV-2 has affinity for neuronally expressed ACE2 receptors, triggering inflammation and ganglionic cell destruction 1
   • One study found 625-fold higher N protein and elevated S protein in esophageal muscle tissue from patients with post-COVID achalasia compared to those with longstanding achalasia 1
   • Viral presence correlated with increased inflammatory markers NLRP3 and TNF 1
   • Other viruses have been implicated in triggering autoimmune responses against inhibitory neurons in the LES 2

Allergic/Eosinophilic Associations

A significant relationship exists between eosinophilic disorders and achalasia:

• Dense accumulation of eosinophils found in muscularis propria of esophagectomy specimens 1
• In a study of 844 achalasia patients, the relative risk of eosinophilic esophagitis (EoE) was 32.9 (95% CI 24.8-42.8) 1
• Risk was higher in patients ≤40 years old 1
• Increased risk also observed for other atopic/allergic disorders 1
• Eosinophils and mast cells produce neuroactive substances that may cause motility disturbances and neuronal destruction 1

Paraneoplastic Phenomenon

Achalasia can occur as a paraneoplastic manifestation in certain malignancies:

• Most commonly associated with lymphoma, lung cancer, and breast cancer (beyond esophageal adenocarcinoma) 1

Genetic Susceptibility

While not a primary cause, genetic factors may predispose individuals:

• Some familial cases have been reported 3
• Genetic susceptibility likely interacts with environmental triggers 2

Clinical Implications of Etiology

Understanding the etiology has important diagnostic and therapeutic implications:

1. Diagnostic Approach:

   • Consider serologic testing for Chagas disease in patients with travel history to Central/South America 1
   • Evaluate for autoimmune conditions, particularly in patients with systemic symptoms 1
   • Consider COVID-19 history in patients with acute-onset symptoms 1
   • Assess for allergic disorders, especially in younger patients 1

2. Treatment Considerations:

   • In patients with comorbid EoE, treating the eosinophilic infiltration may improve esophageal function 1
   • Post-COVID achalasia patients have shown favorable short-term outcomes following myotomy 1
   • The underlying etiology doesn't change the primary treatment approach (reducing LES pressure) but may influence prognosis

Diagnostic Challenges

A fundamental difficulty in diagnosing achalasia is the absence of a specific biomarker:

• Despite known pathology (inflammation of myenteric plexus leading to aganglionosis), diagnosis is not established by biopsy 1
• Diagnosis relies on high-resolution manometry demonstrating absent peristalsis and non-mechanical esophageal outflow obstruction 1
• Disease evolves over variable timespan, making diagnosis challenging in early stages 1

Understanding the multifactorial etiology of achalasia helps clinicians maintain a high index of suspicion in patients with risk factors and provides insights into the pathophysiological basis of this complex disorder.