Achalasia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Achalasia is a motility disorder characterized by insufficiently relaxed lower esophageal sphincter and absent peristalsis. Esophageal motility is coordinated by enteric neurons, hence their degeneration results in above mentioned esophageal motility abnormalities. Mostly the inhibitory neurons which cause LES relaxation by producing nitric oxide are degenerated. Relative sparing of cholinergic neurons results in increased LES tone. Cause of enteric neuron degeneration is still unknown, however, following theories have been suggested:
- Immune ganglionitis is one of the most popular theory, evidence in support of immune degeneration of myenteric neurons are as follows:
- In a study done by Goldblum et al, resected specimens of esophagus in achalasia showed partial to complete loss of myenteric neurons. Inflammation consisting of lymphocytes, eosinophils, plasma cells and mast cells was present in all cases.[1] Clark et al found that nature of the above mentioned lymphocytic infiltrate consisted of activated cytotoxic T cells, further strengthening the immune nature of the disease.[2]
- Complement activation has also been proved to involved in pathogenesis of achalasia.[3]
- Antibodies to myenteric neurons have been found in serum of patients with achalasia.[4] Presence of HLA class II genes such as HLA DQA1*0103 and DQB1*0603 alleles has been shown to predispose patients to develop anti-neuronal antibodies.[5] However, Moses et al showed that these antibodies development could be secondary to injury resulting from achalasia and may not be the primary causative factor.[6]
- Autoimmune
- Two-thirds of patients have auto-antibodies directed against DARP-32, a dopamine-carrying protein on the surface of cells in the myenteric plexus. Achalasia is also associated with HLA-DQw1.
- Infection
- Several diseases have been associated with motor abnormalities similar or identical to those of achalasia and have been called pseudoachalasia.
- Malignancy (especially gastric, lung, lymphoma and pancreatic) causes achalasia by either direct invasion of the esophageal neuronal plexus, or via the release of unidentified evil humors that act in a paraneoplastic function.
- Chagas disease: Trypanosoma cruzi directly infects the esophagus.
- Amyloidosis, sarcoidosis, eosinophilic gastroenteritis, neurofibromatosis, juvenile Sjögren’s, Ogilvie’s syndrome and Anderson-Fabry’s disease have also been associated with pseudoachalasia.
- Autoimmune
Gross Pathology
Pathological examination reveals a defect in the nerves that control the motility of the esophagus (the myenteric plexus). The esophagus is dilated and hypertrophied. In Chagas disease, the ganglion cells are destroyed by Trypanosoma cruzi, the causative parasite.[7]
References
- ↑ Goldblum JR, Whyte RI, Orringer MB, Appelman HD (1994). "Achalasia. A morphologic study of 42 resected specimens". Am J Surg Pathol. 18 (4): 327–37. PMID 8141427.
- ↑ Clark SB, Rice TW, Tubbs RR, Richter JE, Goldblum JR (2000). "The nature of the myenteric infiltrate in achalasia: an immunohistochemical analysis". Am J Surg Pathol. 24 (8): 1153–8. PMID 10935657.
- ↑ Storch WB, Eckardt VF, Junginger T (2002). "Complement components and terminal complement complex in oesophageal smooth muscle of patients with achalasia". Cell Mol Biol (Noisy-le-grand). 48 (3): 247–52. PMID 12030428.
- ↑ Storch WB, Eckardt VF, Wienbeck M, Eberl T, Auer PG, Hecker A; et al. (1995). "Autoantibodies to Auerbach's plexus in achalasia". Cell Mol Biol (Noisy-le-grand). 41 (8): 1033–8. PMID 8747084.
- ↑ Ruiz-de-León A, Mendoza J, Sevilla-Mantilla C, Fernández AM, Pérez-de-la-Serna J, Gónzalez VA; et al. (2002). "Myenteric antiplexus antibodies and class II HLA in achalasia". Dig Dis Sci. 47 (1): 15–9. PMID 11837716.
- ↑ Moses PL, Ellis LM, Anees MR, Ho W, Rothstein RI, Meddings JB; et al. (2003). "Antineuronal antibodies in idiopathic achalasia and gastro-oesophageal reflux disease". Gut. 52 (5): 629–36. PMC 1773656. PMID 12692044.
- ↑ Rubin's Pathology - Clinicopathological Foundations of Medicine. Maryland: Lippincott Williams & Wilkins. 2001. pp. p. 665. ISBN 0-7817-4733-3. Unknown parameter
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