Achalasia pp 9-14 | Cite as

Pathophysiology of Achalasia

  • Wai-Kit LoEmail author
  • Hiroshi Mashimo


Achalasia is a motility disorder of the esophagus, most commonly presenting as dysphagia to solids and liquids, with gradual symptom progression. Pathophysiology arises from degeneration of inhibitory neurons of the lower esophageal sphincter (LES), resulting in unopposed tonicity and poor relaxation ability of the LES. The etiology of primary achalasia is unknown, but may involve viral, genetic, autoimmune, or neurodegenerative causes. Secondary achalasia, or pseudoachalasia, may arise from Chagas disease, malignancy associated with invasive or paraneoplastic disease, or other rare syndromes. Diagnosis is made using esophagogastroduodenoscopy, barium swallow radiography, and esophageal manometry, in order to demonstrate the effects of the underlying pathophysiologic changes and to allow for manometric subtyping which predicts treatment response. Treatment includes mechanical and biochemical methods to disrupt the pathophysiologic process. Complications of untreated disease may include overlying infectious esophagitis, esophageal diverticulosis, megaesophagus, and a slight increase in esophageal cancer risk.


Primary achalasia Lower esophageal sphincter Neuronal degeneration Nitric oxide Vasoactive inhibitory peptide Pseudoachalasia Megaesophagus Aperistalsis 


  1. 1.
    Spiess AE, Kahrilas PJ. Treating achalasia: from whalebone to laparoscope. JAMA. 1998;280(7):638–42.CrossRefPubMedGoogle Scholar
  2. 2.
    Szymanski PT, Chacko TK, Rovner AS, Goyal RK. Differences in contractile protein content and isoforms in phasic and tonic smooth muscles. Am J Physiol. 1998;275:C684–92.PubMedGoogle Scholar
  3. 3.
    Mashimo H, Goyal RK. Physiology of esophageal motility. GI Motility Online. 2006. doi: 10.1038/gimo3.
  4. 4.
    Goyal RK, Chaudhury A. Physiology of normal esophageal motility. J Clin Gastroenterol. 2008;42:610–9.PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Goyal RK, Chaudhury A. Pathogenesis of achalasia: lessons from mutant mice. Gastroenterology. 2010;139(4):1086–90.CrossRefPubMedGoogle Scholar
  6. 6.
    Castagliuolo I, Brun P, Costantini M, Rizzetto C, Palu G, Costantino M, Baldan N, Zaninotto G. Esophageal achalasia: is the herpes simplex virus really innocent? J Gastrointest Surg. 2004;8(1):24–30.CrossRefPubMedGoogle Scholar
  7. 7.
    Robertson CS, Martin BA, Atkinson M. Varicella-zoster virus DNA in the oesophageal myenteric plexus in achalasia. Gut. 1993;34(3):299–302.PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Birgisson S, Galinski MS, Goldblum JR, et al. Achalasia is not associated with measles or known herpes and human papilloma viruses. Dig Dis Sci. 1997;42:300–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Kelly JL, Mulcahy TM, O’Riordain DS, et al. Coexistent Hirschsprung’s disease and esophageal achalasia in male siblings. J Pediatr Surg. 1997;32(12):1809–11.CrossRefPubMedGoogle Scholar
  10. 10.
    Evsyutina YV, Trukhmanov AS, Ivashkin VT. Family case of achalasia cardia: case report and review of literature. World J Gastroenterol. 2014;20(4):1114–8.PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Kallel-Sellami M, Karoui S, Romdhane H, Laddhar L, Serghini M, Boubaker J, Lahmar H, Filali A, Makni S. Circulating antimyenteric autoantibodies in Tunisian patients with idiopathic achalasia. Dis Esophagus. 2013;26(8):782–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Verne GN, Sallustio JE, Eaker EY. Anti-myenteric neuronal antibodies in patients with achalasia: a prospective study. Dig Dis Sci. 1997;42:307–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Wong RK, Maydonovitch CL, Metz SJ, Baker Jr JR. Significant DQw1 association in achalasia. Dig Dis Sci. 1989;34:349–52.CrossRefPubMedGoogle Scholar
  14. 14.
    Moses PL, Ellis LM, Anees MR, Ho W, Rothstein RI, Meddings JB, Sharkey KA, Mawe GM. Antineuronal antibodies in idiopathic achalasia and gastro-oesophageal reflux disease. Gut. 2003;52(5):629–36.PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Qualman SJ, Haupt HM, Yang P, Hamilton SR. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Similarity to Parkinson’s disease. Gastroenterology. 1984;87(4):848–56.PubMedGoogle Scholar
  16. 16.
    Atkinson M, Ogilvie AL, Robertson CS, Smart HL. Vagal function in achalasia of the cardia. Q J Med. 1987;63(240):297–303.PubMedGoogle Scholar
  17. 17.
    De Oliveira RB, Rezende Filho J, Dantas RO, Iazigi N. The spectrum of esophageal motor disorders in Chagas’ disease. Am J Gastroenterol. 1995;90(7):1119–24.PubMedGoogle Scholar
  18. 18.
    Kahrilas PJ, Kishk SM, Helm JF, Dodds WJ, Harig JM, Hogan WJ. Comparison of pseudoachalasia and achalasia. Am J Med. 1987;82(3):439–46.CrossRefPubMedGoogle Scholar
  19. 19.
    Katzka DA, Farrugia G, Arora AS. Achalasia secondary to neoplasia: a disease with a changing differential diagnosis. Dis Esophagus. 2012;25(4):331–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Weber A, Wienker TF, Jung M, et al. Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster. Hum Mol Genet. 1996;5:2061–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Goldblum JR, Rice TW, Richter JE. Histopathologic features in esophagomyotomy specimens from patients with achalasia. Gastroenterology. 1996;111(3):648–54.CrossRefPubMedGoogle Scholar
  23. 23.
    Dodds WJ, Dent J, Hogan WJ, Patel GK, Toouli J, Arndorfer RC. Paradoxical lower esophageal sphincter contraction induced by cholecystokinin-octapeptide in patients with achalasia. Gastroenterology. 1981;80(2):327–33.PubMedGoogle Scholar
  24. 24.
    Holloway RH, Dodds WJ, Helm JF, et al. Integrity of cholinergic innervation to the lower esophageal sphincter in achalasia. Gastroenterology. 1986;90:924–9.PubMedGoogle Scholar
  25. 25.
    Sivarao DV, Mashimo HL, Thatte HS, Goyal RK. Lower esophageal sphincter is achalasic in nNOS−/− and hypotensive in W/Wv mutant mice. Gastroenterology. 2001;121:34–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Eng C. Seminars in medicine of the Beth Israel Hospital, Boston: the RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med. 1996;335:943–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Fritzen R, Bornstein SR, Scherbaum WA. Megaoesophagus in a patient with autoimmune polyglandular syndrome type II. Clin Endocrinol (Oxf). 1996;45:493–8.CrossRefGoogle Scholar
  28. 28.
    Pasricha PJ, Rai R, Ravich WJ, Hendrix TR, Kalloo AN. Botulinum toxin for achalasia: long-term outcome and predictors of response. Gastroenterology. 1996;110(5):1410–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Traube M, Dubovik S, Lange RC, McCallum RW. The role of nifedipine therapy in achalasia: results of a randomized, double-blind, placebo-controlled study. Am J Gastroenterol. 1989;84(10):1259–62.PubMedGoogle Scholar
  30. 30.
    Wen ZH, Gardener E, Wang YP. Nitrates for achalasia. Cochrane Database Syst Rev. 2004;1, CD002299.PubMedGoogle Scholar
  31. 31.
    Bortolotti M, Mari C, Lopilato C, Porrazzo G, Miglioli M. Effects of sildenafil on esophageal motility of patients with idiopathic achalasia. Gastroenterology. 2000;118(2):253–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Ott DJ, Hodge RG, Chen MY, Wu WC, Gelfand DW. Achalasia associated with esophageal diverticula. Prevalence and potential implications. J Clin Gastroenterol. 1994;18(4):343–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology. 2008;135(5):1526–33.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Rohof WO, Salvador R, Annese V, et al. Outcomes of treatment for achalasia depend on manometric subtype. Gastroenterology. 2013;144(4):718–25.CrossRefPubMedGoogle Scholar
  35. 35.
    Eckardt VF, Hoischen T, Bernhard G. Life expectancy, complications, and causes of death in patients with achalasia: results of a 33-year follow-up investigation. Eur J Gastroenterol Hepatol. 2008;20(10):956–60.CrossRefPubMedGoogle Scholar
  36. 36.
    Leeuwenburgh I, Scholten P, Alderliesten J, et al. Long-term esophageal cancer risk in patients with primary achalasia: a prospective study. Am J Gastroenterol. 2010;105(10):2144–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Zendehdel K, Nyren O, Edberg A, Ye W. Risk of esophageal adenocarcinoma in achalasia patients, a retrospective cohort study in Sweden. Am J Gastroenterol. 2011;106(1):57–61.CrossRefPubMedGoogle Scholar
  38. 38.
    Brucher BL, Stein HL, Bartels H, Feussner H, Siewert JR. Achalasia and esophageal cancer: incidence, prevalence, and prognosis. World J Surg. 2001;25(6):745–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of GastroenterologyVA Boston Healthcare System, Harvard Medical SchoolBostonUSA
  2. 2.Division of GastroenterologyVA Boston Healthcare System, Harvard Medical SchoolBostonUSA

Personalised recommendations