Pathogenesis of achalasia cardia

Abstract

Achalasia cardia is one of the common causes of motor dysphagia. Though the disease was first described more than 300 years ago, exact pathogenesis of this condition still remains enigmatic. Pathophysiologically, achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus. In the initial stage, degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine, resulting in high amplitude non-peristaltic contractions (vigorous achalasia); progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body (classic achalasia). Since the initial description, several studies have attempted to explore initiating agents that may cause the disease, such as viral infection, other environmental factors, autoimmunity, and genetic factors. Though Chagas disease, which mimics achalasia, is caused by an infective agent, available evidence suggests that infection may not be an independent cause of primary achalasia. A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins, siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down's syndrome and Parkinson's disease. Polymorphisms in genes encoding for nitric oxide synthase, receptors for vasoactive intestinal peptide, interleukin 23 and the ALADIN gene have been reported. However, studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained. Currently, the disease is believed to be multi-factorial, with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.

Achalasia Is Associated With eNOS4a4a, iNOS22GA, and nNOS29TT Genotypes: A Case-control Study

“…1 Its pathogenesis is still enigmatic. [2][3][4] Genetic factors are likely to be important in its pathogenesis as supported by occasional familial aggregation, concordance among monozygotic twins and reports on association between achalasia and Hirshsprung's disease, a similar condition with genetic basis. [5][6][7] Esophageal aperistalsis and incomplete lower esophageal sphincter (LES) relaxation, the characteristic features of achalasia, result from degeneration of the ganglion cells in the myenteric plexus.…”

“…9 Nitric oxide (NO) is the most important inhibitory neurotransmitter of the esophageal myenteric plexus; it progressively delays muscular contraction in the distal esophagus preventing simultaneous contraction and relaxes LES during swallowing in healthy persons. 3 Degeneration of NO-containing neurons, therefore, causes simultaneous contraction in the esophageal body and failure of swallow-induced LES relaxation. 9,10 NO is synthesized by NO synthase (NOS), which has 3 isoforms, namely, endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS).…”

First Identified Case in Literature: Association of Achalasia and Celiac Diseases

“…An autoimmune etiology for AD has been consid¬ered because of the presence of neural inflammation in the absence of conclusive evidence of infection. Studies have demonstrated inflammatory cell infiltrate of the myen¬teric plexus in 90%-100% of esophageal specimens from AD patients [6]. Storch et al suggested a role of autoimmunity by demonstrating a higher prevalence of anti-myenteric autoantibody in AD (64%) [7].…”

Achalasia and thyroid disease: possible autoimmune connection?

“…in the serum of a subgroup of patients with achalasia (8)(9)(10)13). A cluster consisting of varied autoimmune diseases has been linked to achalasia: myasthenia gravis, polymyositis, autoimmune thyroid disease, among others, contributing to the argument that autoimmunity may be a cause for some idiopathic achalasia (17)(18)(19).…”

“…However, some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. Specifically, higher genotypic frequency of the human leukocyte antigen (HLA)-DQw1, DQA1*0101, DQA1*103, DQB1*0602, and DQB1*0603 alleles were observed in achalasia patients compared with controls (7,8,(10)(11)(12)(13). Descriptions of inflammatory infiltration in the affected regions of the esophagus in achalasia led to speculation of an autoimmune pathogenesis.…”