title: The spectrum of achalasia: lessons from studies of pathophysiology and high-resolution manometry.
abstract: High-resolution manometry and recently described analysis algorithms, summarized in the Chicago Classification, have increased the recognition of achalasia. It has become apparent that the cardinal feature of achalasia, impaired lower esophageal sphincter relaxation, can occur in several disease phenotypes: without peristalsis, with premature (spastic) distal esophageal contractions, with panesophageal pressurization, or with peristalsis. Any of these phenotypes could indicate achalasia; however, without a disease-specific biomarker, no manometric pattern is absolutely specific. Laboratory studies indicate that achalasia is an autoimmune disease in which esophageal myenteric neurons are attacked in a cell-mediated and antibody-mediated immune response against an uncertain antigen. This autoimmune response could be related to infection of genetically predisposed subjects with herpes simplex virus 1, although there is substantial heterogeneity among patients. At one end of the spectrum is complete aganglionosis in patients with end-stage or fulminant disease. At the opposite extreme is type III (spastic) achalasia, which has no demonstrated neuronal loss but only impaired inhibitory postganglionic neuron function; it is often associated with accentuated contractility and could be mediated by cytokine-induced alterations in gene expression. Distinct from these extremes is progressive plexopathy, which likely arises from achalasia with preserved peristalsis and then develops into type II achalasia and then type I achalasia. Variations in its extent and rate of progression are likely related to the intensity of the cytotoxic T-cell assault on the myenteric plexus. Moving forward, we need to integrate the knowledge we have gained into treatment paradigms that are specific for individual phenotypes of achalasia and away from the one-size-fits-all approach.
authors: Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: p-kahrilas@northwestern.edu.
authors: Peter J
authors: PJ
authors: Kahrilas
authors: Guy
authors: G
authors: Boeckxstaens
mesh_terms: D000465:Algorithms; D018450:Disease Progression; D004931:Esophageal Achalasia / Q000145:classification* / Q000503:physiopathology*; D006801:Humans; D008365:Manometry / Q000379:methods*; D009119:Muscle Contraction / Q000502:physiology; D009126:Muscle Relaxation / Q000502:physiology; D010528:Peristalsis / Q000502:physiology; D010641:Phenotype
keywords: Achalasia; Dysphagia; EGJ; EPT; Esophageal Motility; HSV-1; IRP; LES; Pathogenesis; TLESR; esophageal pressure topography; esophagogastric junction; herpes simplex virus 1; integrated relaxation pressure; lower esophageal sphincter; transient lower esophageal sphincter relaxation
references: Neurogastroenterol Motil. 2011 Jun;23(6):502-e197
references: 21303431
references: Am J Gastroenterol. 2001 Feb;96(2):373-9
references: 11232678
references: Am J Med. 1987 Mar;82(3):439-46
references: 3548347
references: Proc Natl Acad Sci U S A. 1984 Jun;81(11):3595-9
references: 6587375
references: Dig Dis Sci. 1985 Oct;30(10):941-5
references: 4028910
references: Neurogastroenterol Motil. 2007 Mar;19(3):203-10
references: 17300290
references: Gut. 2006 Mar;55(3):319-26
references: 16105888
references: Am J Physiol. 1973 Dec;225(6):1265-70
references: 4760438
references: Gastroenterology. 1985 Oct;89(4):779-84
references: 4029557
references: J Clin Gastroenterol. 2011 Oct;45(9):775-9
references: 21778895
references: Am J Physiol. 1990 Apr;258(4 Pt 1):G624-30
references: 2333975
references: Gastroenterology. 2001 Mar;120(4):789-98
references: 11231931
references: J Gastrointest Surg. 2004 Jan;8(1):24-30; discussion 30
references: 14746832
references: Gastroenterology. 2006 Dec;131(6):1725-33
references: 17087957
references: Am J Physiol. 1993 Dec;265(6 Pt 1):G1098-1107
references: 8279561
references: Gastroenterology. 1995 Aug;109(2):601-10
references: 7615211
references: Surgery. 1999 May;125(5):498-503
references: 10330937
references: Am J Gastroenterol. 2001 Dec;96(12):3258-67
references: 11774934
references: Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G329-34
references: 17023549
references: Am J Physiol. 1989 Jan;256(1 Pt 1):G139-44
references: 2912145
references: J Neurogastroenterol Motil. 2013 Apr;19(2):126-36
references: 23667744
references: Am J Physiol Gastrointest Liver Physiol. 2012 Feb 1;302(3):G389-96
references: 22114118
references: Am J Gastroenterol. 1995 Jul;90(7):1119-24
references: 7611209
references: Am J Dig Dis. 1968 Apr;13(4):320-34
references: 4966899
references: Am J Physiol. 1985 Mar;248(3 Pt 1):G342-6
references: 3976893
references: Gastroenterology. 2008 May;134(5):1322-31
references: 18384786
references: Am J Physiol. 1993 Oct;265(4 Pt 1):G660-71
references: 7694477
references: Cell. 1994 Sep 23;78(6):915-8
references: 7522969
references: Am J Physiol. 1980 Jun;238(6):G485-90
references: 7386632
references: Am J Physiol. 1991 Sep;261(3 Pt 1):G401-6
references: 1887888
references: Gut. 2012 Apr;61(4):613-21
references: 21816959
references: Dis Esophagus. 2013 Jul;26(5):470-4
references: 22816880
references: Proc Soc Exp Biol Med. 1979 Nov;162(2):354-8
references: 515013
references: Dig Dis Sci. 2002 Jan;47(1):15-9
references: 11837716
references: Cell Mol Biol (Noisy-le-grand). 2002 May;48(3):247-52
references: 12030428
references: Am J Gastroenterol. 2008 Jul;103(7):1598-609
references: 18557707
references: Gastroenterology. 1976 Jul;71(1):62-7
references: 1278651
references: Gut. 1993 Mar;34(3):299-302
references: 8386130
references: Neurogastroenterol Motil. 2009 Dec;21(12):1294-e123
references: 19552630
references: Gastroenterology. 2005 Jan;128(1):207-8
references: 15633137
references: Gastroenterology. 2013 Apr;144(4):718-25; quiz e13-4
references: 23277105
references: Am J Surg Pathol. 1994 Apr;18(4):327-37
references: 8141427
references: Neurogastroenterol Motil. 2007 Apr;19(4):263-9
references: 17391242
references: Dig Dis Sci. 1995 Apr;40(4):859-64
references: 7720482
references: J Gastroenterol Hepatol. 1996 May;11(5):478-85
references: 8743921
references: Am J Physiol. 1991 Oct;261(4 Pt 1):G677-84
references: 1928353
references: Gastroenterology. 1991 Jan;100(1):137-42
references: 1845756
references: Gastroenterology. 1985 Oct;89(4):843-51
references: 4029565
references: Exp Brain Res. 1970;11(1):48-74
references: 5458717
references: JAMA Surg. 2013 Feb;148(2):157-64
references: 23426591
references: J Surg Res. 2007 Nov;143(1):177-82
references: 17950090
references: Gastroenterology. 1996 Sep;111(3):648-54
references: 8780569
references: Am J Med. 2000 Mar 6;108 Suppl 4a:3S-7S
references: 10718444
references: Gastroenterology. 2010 Mar;138(3):1091-101.e1-5
references: 19732773
references: Gastroenterology. 1983 Oct;85(4):890-9
references: 6884712
references: J Neurophysiol. 1984 Dec;52(6):1169-80
references: 6520630
references: Neurogastroenterol Motil. 2012 Dec;24(12):1069-e561
references: 22788116
references: Am J Physiol Gastrointest Liver Physiol. 2007 Oct;293(4):G878-85
references: 17690172
references: Am J Gastroenterol. 2008 Jul;103(7):1610-2
references: 18557706
references: Am J Clin Pathol. 1983 Mar;79(3):319-25
references: 6829502
references: J Auton Nerv Syst. 1995 Apr 8;52(2-3):99-105
references: 7542293
references: J Appl Physiol Respir Environ Exerc Physiol. 1982 Jul;53(1):30-9
references: 7118646
references: Clin Gastroenterol Hepatol. 2011 Dec;9(12):1104-6
references: 21839711
references: Dis Esophagus. 2009;22(5):382-5
references: 19207553
references: Aliment Pharmacol Ther. 1996 Dec;10(6):875-82
references: 8971283
references: Am J Surg Pathol. 2000 Aug;24(8):1153-8
references: 10935657
references: Gastroenterology. 1993 Nov;105(5):1362-9
references: 8224640
references: Gastroenterology. 2005 Jan;128(1):209-24
references: 15633138
references: Dig Dis Sci. 2005 Sep;50(9):1605-10
references: 16133957
references: Gastroenterology. 2009 Jun;136(7):2214-25.e1-3
references: 19505425
references: Dis Esophagus. 2013 Jan;26(1):14-21
references: 22309323
references: Gut. 2003 May;52(5):629-36
references: 12692044
references: Dysphagia. 1993 Fall;8(4):384-6
references: 8269733
references: Neurogastroenterol Motil. 2008 Aug;20(8):869-76
references: 18452508
references: Am J Gastroenterol. 2012 Jan;107(1):37-45
references: 21931377
references: Am J Gastroenterol. 2007 Jan;102(1):137-45
references: 17266691
references: J Am Coll Surg. 2011 Jul;213(1):155-61; discussion 162-3
references: 21435920
references: Gastroenterology. 1978 May;74(5 Pt 1):835-40
references: 640338
references: J Biomech. 2009 Aug 7;42(11):1604-9
references: 19481212
references: J Clin Invest. 1984 Apr;73(4):963-7
references: 6142903
references: Gastroenterology. 1982 Feb;82(2):301-8
references: 7054030
references: J Gastrointest Surg. 2007 Nov;11(11):1403-9
references: 17786525
references: Gastroenterology. 1987 Mar;92(3):643-50
references: 3817387
references: Am J Gastroenterol. 1999 Sep;94(9):2357-62
references: 10483991
references: Neurogastroenterol Motil. 2012 Mar;24 Suppl 1:57-65
references: 22248109
references: Am J Gastroenterol. 1995 May;90(5):713-7
references: 7733074
references: Gastroenterology. 1992 Aug;103(2):377-82
references: 1634056
references: Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G397-405
references: 19520741
references: J Clin Gastroenterol. 1986 Apr;8(2):131-4
references: 3745845
references: Gastroenterology. 2010 Jul;139(1):102-11
references: 20381493
references: Am J Gastroenterol. 2000 Oct;95(10):2720-30
references: 11051340
references: Gastroenterology. 1991 Sep;101(3):657-63
references: 1860630
references: Dig Liver Dis. 2011 Feb;43(2):116-20
references: 20943447
references: Clin Gastroenterol Hepatol. 2013 Feb;11(2):131-7; quiz e15
references: 23078890
references: Am J Physiol. 1985 Nov;249(5 Pt 1):G586-91
references: 4061647
references: J Clin Gastroenterol. 1991 Oct;13(5):554-8
references: 1744393
references: Gastroenterology. 1995 Sep;109(3):789-99
references: 7657107
references: Am J Physiol. 1981 Apr;240(4):G290-6
references: 6784581
references: Dig Dis Sci. 1997 Feb;42(2):300-6
references: 9052510
references: Dig Dis Sci. 1989 Dec;34(12):1894-9
references: 2689111
references: Cell Mol Biol (Noisy-le-grand). 1995 Dec;41(8):1033-8
references: 8747084
references: J Clin Invest. 1975 May;55(5):1119-26
references: 164484
references: J Clin Gastroenterol. 2010 Jul;44(6):407-10
references: 19834336
references: J Physiol. 1977 Dec;273(3):647-64
references: 604452
references: Br J Surg. 1995 Nov;82(11):1532-4
references: 8535811
references: Neurogastroenterol Motil. 2013 Jul;25(7):e485-94
references: 23634870
references: Am J Otolaryngol. 1980 Nov;1(5):440-6
references: 7457764
references: Gastroenterology. 2008 Nov;135(5):1526-33
references: 18722376
references: Am J Physiol. 1984 Mar;246(3 Pt 1):G243-7
references: 6703056
references: Am J Physiol. 1990 Feb;258(2 Pt 1):G208-15
references: 2305886
references: Am J Physiol. 1978 Dec;235(6):E709-13
references: 736131