Achalasia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Twinkle Singh, M.B.B.S. [2], Ahmed Younes M.B.B.CH [3]
Overview
Achalasia is caused by degeneration of myenteric neurons, resulting from immune system activation. Evidence for antigens responsible for such immune system activation still remain inconclusive, however, viral antigens such as HSV-1, HPV, measles have been shown to play a role in achalasia pathogenesis. Genetic factors such as HLA class II alleles also predispose to achalasia development.
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 the 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.[1] The cause of enteric neuron degeneration is still unknown, however, the following theories have been suggested:
- Immune ganglionitis is one of the most popular theories
- In a study done by Goldblum et al, resected specimens of the esophagus in achalasia showed partial to complete loss of myenteric neurons. An Inflammation consisting of lymphocytes, eosinophils, plasma cells and mast cells was present in all of the cases.[2] Clark et al found that the above mentioned lymphocytic infiltrate consisted of activated cytotoxic T cells, further strengthening the immune nature of the disease.[3]
- Complement activation has also been proved to be involved in the pathogenesis of achalasia.[4]
- Antibodies to myenteric neurons have been found in the serum of patients with achalasia.[5] The presence of HLA class II genes such as HLA DQA1*0103 and DQB1*0603 alleles has been shown to predispose the patients to develop anti-neuronal antibodies.[6] However, Moses et al showed that the development of these antibodies could be secondary to an injury resulting from achalasia and may not be the primary causative factor.[7]
- Antigens responsible for the above mentioned immune response are still not known, however, viral antigens such as HSV-1, HPV and measles viruses have been suggested to be involved. These are some proofs in favor of HSV-1 antigen involvement in achalasia pathogenesis:
- It has been shown that immune cells involved in neuronal degeneration in LES are reactive to HSV-1.[8][9]
- In one study, HSV-1 DNA was found in all the patients with achalasia and also in the control population without achalasia. It was then suggested that genetically predisposed individuals having a latent HSV-1 infection develop an aberrant immune response to the degenerating neurons in LES and causing achalasia.[10]
Proposed hypothesis for achalasia development:[11]
| Initial viral infection with HSV1 or HPV | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genetic predisposition with HLA DQA1*0103 and DQB1*0603 alleles | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No achalasia | Aberrant immune response | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Achalsia development | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The above algorithm was adapted from a study done by Boeckxstaens GE.[10][11]
- Few studies found no evidence of HSV-1, HPV or measles viral infections in patients with achalasia, hence, The involvement of above mention viral antigens in the development of achalasia remain inconclusive.[12][13]
- The following genetic factors have also been suggested to be involved with achalasia development:[11]
- HLA class II molecules
- Vasoactive intestinal peptide[14]
- KIT[15]
- Interleukin 23 receptor[16]
- Several diseases have been associated with motor abnormalities similar or identical to those of achalasia and have been called pseudoachalasia.
- Malignancy causing achalasia by direct infiltration of the esophageal neuronal plexus.
- 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.
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.[17]
References
- ↑ Holloway RH, Dodds WJ, Helm JF, Hogan WJ, Dent J, Arndorfer RC (1986). "Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia". Gastroenterology. 90 (4): 924–9. PMID 3949120.
- ↑ 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.
- ↑ Facco M, Brun P, Baesso I, Costantini M, Rizzetto C, Berto A; et al. (2008). "T cells in the myenteric plexus of achalasia patients show a skewed TCR repertoire and react to HSV-1 antigens". Am J Gastroenterol. 103 (7): 1598–609. doi:10.1111/j.1572-0241.2008.01956.x. PMID 18557707.
- ↑ Castagliuolo I, Brun P, Costantini M, Rizzetto C, Palù G, Costantino M; et al. (2004). "Esophageal achalasia: is the herpes simplex virus really innocent?". J Gastrointest Surg. 8 (1): 24–30, discussion 30. PMID 14746832.
- ↑ 10.0 10.1 Boeckxstaens GE (2008). "Achalasia: virus-induced euthanasia of neurons?". Am J Gastroenterol. 103 (7): 1610–2. doi:10.1111/j.1572-0241.2008.01967.x. PMID 18557706.
- ↑ 11.0 11.1 11.2 Boeckxstaens GE, Zaninotto G, Richter JE (2014). "Achalasia". Lancet. 383 (9911): 83–93. doi:10.1016/S0140-6736(13)60651-0. PMID 23871090.
- ↑ Birgisson S, Galinski MS, Goldblum JR, Rice TW, Richter JE (1997). "Achalasia is not associated with measles or known herpes and human papilloma viruses". Dig Dis Sci. 42 (2): 300–6. PMID 9052510.
- ↑ Niwamoto H, Okamoto E, Fujimoto J, Takeuchi M, Furuyama J, Yamamoto Y (1995). "Are human herpes viruses or measles virus associated with esophageal achalasia?". Dig Dis Sci. 40 (4): 859–64. PMID 7720482.
- ↑ Paladini F, Cocco E, Cascino I, Belfiore F, Badiali D, Piretta L; et al. (2009). "Age-dependent association of idiopathic achalasia with vasoactive intestinal peptide receptor 1 gene". Neurogastroenterol Motil. 21 (6): 597–602. doi:10.1111/j.1365-2982.2009.01284.x. PMID 19309439.
- ↑ Alahdab YO, Eren F, Giral A, Gunduz F, Kedrah AE, Atug O; et al. (2012). "Preliminary evidence of an association between the functional c-kit rs6554199 polymorphism and achalasia in a Turkish population". Neurogastroenterol Motil. 24 (1): 27–30. doi:10.1111/j.1365-2982.2011.01793.x. PMID 21951831.
- ↑ de León AR, de la Serna JP, Santiago JL, Sevilla C, Fernández-Arquero M, de la Concha EG; et al. (2010). "Association between idiopathic achalasia and IL23R gene". Neurogastroenterol Motil. 22 (7): 734–8, e218. doi:10.1111/j.1365-2982.2010.01497.x. PMID 20367798.
- ↑ 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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