Advertisement
Mayo Clinic Proceedings Home

Pathogenesis of Gastroesophageal Reflux and Barrett Esophagus

      Barrett esophagus is a metaplastic condition that affects the lower esophagus and is a complication of gastroesophageal reflux disease (GERD). Under normal circumstances, the reflux of gastric contents into the esophagus is prevented by a complex barrier at the esophagogastric junction. Dysfunction of the lower esophageal sphincter and the presence of a hiatal hernia lead to failure of this barrier. Esophageal mucosal damage results from the chronic exposure of the esophageal mucosa to gastroduodenal contents and the lack of an effective mucosal defense. This article is an overview of the dysfunction of the esophagogastric junction that leads to GERD. The role of the contents of the reflux and that of Helicobacter pylori infection in the pathogenesis of Barrett esophagus are also summarized.
      EG (esophagogastric), GERD (gastroesophageal reflux disease), LES (lower esophageal sphincter), NANC (nonadrenergic, noncholinergic)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Liebermann-Meffert D
        • Allgower M
        • Schmid P
        • Blum AL
        Muscular equivalent of the lower esophageal sphincter.
        Gastroenterology. 1979; 76: 31-38
        • Mittal RK
        • Balaban DH
        The esophagogastric junction.
        N Engl J Med. 1997; 336: 924-932
        • Seelig Jr, LL
        • Goyal RK
        Morphological evaluation of opossum lower esophageal sphincter.
        Gastroenterology. 1978; 75: 51-58
        • Christensen J
        • Roberts RL
        Differences between esophageal body and lower esophageal sphincter in mitochondria of smooth muscle in opossum.
        Gastroenterology. 1983; 85: 650-656
        • Christensen J
        • Conklin JL
        • Freeman BW
        Physiologic specialization at esophagogastric junction in three species.
        Am J Physiol. 1973; 225: 1265-1270
        • Goyal RK
        • Rattan S
        Genesis of basal sphincter pressure: effect of tetrodotoxin on lower esophageal sphincter pressure in opossum in vivo.
        Gastroenterology. 1976; 71: 62-67
        • DiMarino AJ
        • Cohen S
        The adrenergic control of lower esophageal sphincter function: an experimental model of denervation super-sensitivity.
        J Clin Invest. 1973; 52: 2264-2271
        • Fournet J
        • Snape Jr, WJ
        • Cohen S
        Sympathetic control of lower esophageal sphincter function in the cat: action of direct cervical and splanchnic nerve stimulation.
        J Clin Invest. 1979; 63: 562-570
        • Kawahara H
        • Blackshaw LA
        • Lehmann A
        • Dent J
        Responses of the rat lower oesophageal sphincter (LOS) to vagal efferent activation.
        Neurogastroenterol Motil. 1997; 9: 85-97
        • Paterson WG
        • Anderson MA
        • Anand N
        Pharmacological characterization of lower esophageal sphincter relaxation induced by swallowing, vagal efferent nerve stimulation, and esophageal distention.
        Can J Physiol Pharmacol. 1992; 70: 1011-1015
        • Blackshaw LA
        • Haupt JA
        • Omari T
        • Dent J
        Vagal and sympathetic influences on the ferret lower oesophageal sphincter.
        J Auton Nerv Syst. 1997; 66: 179-188
        • Murray J
        • Du C
        • Ledlow A
        • Bates JN
        • Conklin JL
        Nitric oxide: mediator of nonadrenergic noncholinergic responses of opossum esophageal muscle.
        Am J Physiol. 1991; 261: G401-G406
        • Murray JA
        • Ledlow A
        • Launspach J
        • Evans D
        • Loveday M
        • Conklin JL
        The effects of recombinant human hemoglobin on esophageal motor functions in humans.
        Gastroenterology. 1995; 109: 1241-1248
        • Dodds WJ
        • Dent J
        • Hogan WJ
        • et al.
        Mechanisms of gastroesophageal reflux in patients with reflux esophagitis.
        N Engl J Med. 1982; 307: 1547-1552
        • Mittal RK
        • McCallum RW
        Characteristics and frequency of transient relaxations of the lower esophageal sphincter in patients with reflux esophagitis.
        Gastroenterology. 1988; 95: 593-599
        • Dent J
        • Holloway RH
        • Toouli J
        • Dodds WJ
        Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux.
        Gut. 1988; 29: 1020-1028
        • Mittal RK
        • Holloway RH
        • Penagini R
        • Blackshaw LA
        • Dent J
        Transient lower esophageal sphincter relaxation.
        Gastroenterology. 1995; 109: 601-610
        • Kahrilas PJ
        • Shi G
        • Manka M
        • Joehl RJ
        Increased frequency of transient lower esophageal sphincter relaxation induced by gastric distention in reflux patients with hiatal hernia.
        Gastroenterology. 2000; 118: 688-695
        • Holloway RH
        • Hongo M
        • Berger K
        • McCallum RW
        Gastric distention: a mechanism for postprandial gastroesophageal reflux.
        Gastroenterology. 1985; 89: 779-784
        • Schoeman MN
        • Tippett MD
        • Akkermans LM
        • Dent J
        • Holloway RH
        Mechanisms of gastroesophageal reflux in ambulant healthy human subjects.
        Gastroenterology. 1995; 108: 83-91
        • Sloan S
        • Rademaker AW
        • Kahrilas PJ
        Determinants of gastroesophageal junction incompetence: hiatal hernia, lower esophageal sphincter, or both?.
        Ann Intern Med. 1992; 117: 977-982
        • Cadiot G
        • Bruhat A
        • Rigaud D
        • et al.
        Multivariate analysis of pathophysiological factors in reflux oesophagitis.
        Gut. 1997; 40: 167-174
        • Kahrilas PJ
        Anatomy and physiology of the gastroesophageal junction.
        Gastroenterol Clin North Am. 1997; 26: 467-486
        • Moss SF
        • Arnold R
        • Tytgat GN
        • et al.
        Consensus Statement for Management of Gastroesophageal Reflux Disease: result of workshop meeting at Yale University School of Medicine, Department of Surgery, November 16 and 17, 1997.
        J Clin Gastroenterol. 1998; 27: 6-12
        • Mittal RK
        Hiatal hernia: myth or reality?.
        Am J Med. 1997; 103: 33S-39S
        • Mittal RK
        • Lange RC
        • McCallum RW
        Identification and mechanism of delayed esophageal acid clearance in subjects with hiatus hernia.
        Gastroenterology. 1987; 92: 130-135
        • Sloan S
        • Kahrilas PJ
        Impairment of esophageal emptying with hiatal hernia.
        Gastroenterology. 1991; 100: 596-605
        • Kahrilas PJ
        • Wu S
        • Lin S
        • Pouderoux P
        Attenuation of esophageal shortening during peristalsis with hiatus hernia.
        Gastroenterology. 1995; 109: 1818-1825
        • Vaezi MF
        • Singh S
        • Richter JE
        Role of acid and duodenogastric reflux in esophageal mucosal injury: a review of animal and human studies.
        Gastroenterology. 1995; 108: 1897-1907
        • Vaezi MF
        • Richter JE
        Synergism of acid and duodenogastroesophageal reflux in complicated Barrett's esophagus.
        Surgery. 1995; 117: 699-704
        • Champion G
        • Richter JE
        • Vaezi MF
        • Singh S
        • Alexander R
        Duodenogastroesophageal reflux: relationship to pH and importance in Barrett's esophagus.
        Gastroenterology. 1994; 107: 747-754
        • Hirschowitz BI
        A critical analysis, with appropriate controls, of gastric acid and pepsin secretion in clinical esophagitis.
        Gastroenterology. 1991; 101: 1149-1158
        • Miller LS
        • Vinayek R
        • Frucht H
        • Gardner JD
        • Jensen RT
        • Maton PN
        Reflux esophagitis in patients with Zollinger-Ellison syndrome.
        Gastroenterology. 1990; 98: 341-346
        • Collen MJ
        • Johnson DA
        • Sheridan MJ
        Basal acid output and gastric acid hypersecretion in gastroesophageal reflux disease: correlation with ranitidine therapy.
        Dig Dis Sci. 1994; 39: 410-417
        • Collen MJ
        • Lewis JH
        • Benjamin SB
        Gastric acid hypersecretion in refractory gastroesophageal reflux disease.
        Gastroenterology. 1990; 98: 654-661
        • McCallum RW
        • Berkowitz DM
        • Lerner E
        Gastric emptying in patients with gastroesophageal reflux.
        Gastroenterology. 1981; 80: 285-291
        • Maddern GJ
        • Chatterton BE
        • Collins PJ
        • Horowitz M
        • Shearman DJ
        • Jamieson GG
        Solid and liquid gastric emptying in patients with gastro-oesophageal reflux.
        Br J Surg. 1985; 72: 344-347
        • Shay SS
        • Eggli D
        • McDonald C
        • Johnson LF
        Gastric emptying of solid food in patients with gastroesophageal reflux.
        Gastroenterology. 1987; 92: 459-465
        • Keshavarzian A
        • Bushnell DL
        • Sontag S
        • Yegelwel EJ
        • Smid K
        Gastric emptying in patients with severe reflux esophagitis.
        Am J Gastroenterol. 1991; 86: 738-742
        • Helm JF
        • Dodds WJ
        • Pelc LR
        • Palmer DW
        • Hogan WJ
        • Teeter BC
        Effect of esophageal emptying and saliva on clearance of acid from the esophagus.
        N Engl J Med. 1984; 310: 284-288
        • Kahrilas PJ
        • Dodds WJ
        • Hogan WJ
        • Kern M
        • Arndorfer RC
        • Reece A
        Esophageal peristaltic dysfunction in peptic esophagitis.
        Gastroenterology. 1986; 91: 897-904
        • Eastwood GL
        • Castell DO
        • Higgs RH
        Experimental esophagitis in cats impairs lower esophageal sphincter pressure.
        Gastroenterology. 1975; 69: 146-153
        • Eckardt VF
        Does healing of esophagitis improve esophageal motor function?.
        Dig Dis Sci. 1988; 33: 161-165
        • Howard JM
        • Reynolds RP
        • Frei JV
        • et al.
        Macroscopic healing of esophagitis does not improve esophageal motility.
        Dig Dis Sci. 1994; 39: 648-654
        • Kongara KR
        • Soffer EE
        Saliva and esophageal protection.
        Am J Gastroenterol. 1999; 94: 1446-1452
        • Orlando RC
        Mechanisms of reflux-induced epithelial injuries in the esophagus.
        Am J Med. 2000; 108: 104S-108S
        • Vitale GC
        • Cheadle WG
        • Patel B
        • Sadek SA
        • Michel ME
        • Cuschieri A
        The effect of alcohol on nocturnal gastroesophageal reflux.
        JAMA. 1987; 258: 2077-2079
        • Nebel OT
        • Fornes MF
        • Castell DO
        Symptomatic gastroesophageal reflux: incidence and precipitating factors.
        Am J Dig Dis. 1976; 21: 953-956
        • Mayer EM
        • Grabowski CJ
        • Fisher RS
        Effects of graded doses of alcohol upon esophageal motor function.
        Gastroenterology. 1978; 75: 1133-1136
        • Schindlbeck NE
        • Heinrich C
        • Dendorfer A
        • Pace F
        • Muller-Lissner SA
        Influence of smoking and esophageal intubation on esophageal pH-metry.
        Gastroenterology. 1987; 92: 1994-1997
        • Waring JP
        • Eastwood TF
        • Austin JM
        • Sanowski RA
        The immediate effects of cessation of cigarette smoking on gastroesophageal reflux.
        Am J Gastroenterol. 1989; 84: 1076-1078
        • Kadakia SC
        • Kikendall JW
        • Maydonovitch C
        • Johnson LF
        Effect of cigarette smoking on gastroesophageal reflux measured by 24-h ambulatory esophageal pH monitoring.
        Am J Gastroenterol. 1995; 90: 1785-1790
        • Kahrilas PJ
        • Gupta RR
        Mechanisms of acid reflux associated with cigarette smoking.
        Gut. 1990; 31: 4-10
        • Pehl C
        • Pfeiffer A
        • Wendl B
        • Nagy I
        • Kaess H
        Effect of smoking on the results of esophageal pH measurement in clinical routine.
        J Clin Gastroenterol. 1997; 25: 503-506
        • Spechler SJ
        • Goyal RK
        Barrett's esophagus.
        N Engl J Med. 1986; 315: 362-371
        • Bremner CG
        • Lynch VP
        • Ellis Jr, FH
        Barrett's esophagus: congenital or acquired? an experimental study of esophageal mucosal regeneration in the dog.
        Surgery. 1970; 68: 209-216
        • Li H
        • Walsh TN
        • O'Dowd G
        • Gillen P
        • Byrne PJ
        • Hennessy TP
        Mechanisms of columnar metaplasia and squamous regeneration in experimental Barrett's esophagus.
        Surgery. 1994; 115: 176-181
        • Gillen P
        • Keeling P
        • Byrne PJ
        • West AB
        • Hennessy TP
        Experimental columnar metaplasia in the canine oesophagus.
        Br J Surg. 1988; 75: 113-115
        • Coenraad M
        • Masclee AA
        • Straathof JW
        • Ganesh S
        • Griffioen G
        • Lamers CB
        Is Barrett's esophagus characterized by more pronounced acid reflux than severe esophagitis?.
        Am J Gastroenterol. 1998; 93: 1068-1072
        • Iascone C
        • DeMeester TR
        • Little AG
        • Skinner DB
        Barrett's esophagus: functional assessment, proposed pathogenesis, and surgical therapy.
        Arch Surg. 1983; 118: 543-549
        • Neumann CS
        • Cooper BT
        24 hour ambulatory oesophageal pH monitoring in uncomplicated Barrett's oesophagus.
        Gut. 1994; 35: 1352-1355
        • Singh P
        • Taylor RH
        • Colin-Jones DG
        Esophageal motor dysfunction and acid exposure in reflux esophagitis are more severe if Barrett's metaplasia is present.
        Am J Gastroenterol. 1994; 89: 349-356
        • Oberg S
        • DeMeester TR
        • Peters JH
        • et al.
        The extent of Barrett's esophagus depends on the status of the lower esophageal sphincter and the degree of esophageal acid exposure.
        J Thorac Cardiovasc Surg. 1999; 117: 572-580
        • Cameron AJ
        Barrett's esophagus: prevalence and size of hiatal hernia.
        Am J Gastroenterol. 1999; 94: 2054-2059
        • Mulholland MW
        • Reid BJ
        • Levine DS
        • Rubin CE
        Elevated gastric acid secretion in patients with Barrett's metaplastic epithelium.
        Dig Dis Sci. 1989; 34: 1329-1334
        • Collen MJ
        • Johnson DA
        Correlation between basal acid output and daily ranitidine dose required for therapy in Barrett's esophagus.
        Dig Dis Sci. 1992; 37: 570-576
        • Hirschowitz BI
        Gastric acid and pepsin secretion in patients with Barrett's esophagus and appropriate controls.
        Dig Dis Sci. 1996; 41: 1384-1391
        • Savarino V
        • Mela GS
        • Zentilin P
        • et al.
        Time pattern of gastric acidity in Barrett's esophagus.
        Dig Dis Sci. 1996; 41: 1379-1383
        • Johnson DA
        • Winters C
        • Spurling TJ
        • Chobanian SJ
        • Cattau Jr, EL
        Esophageal acid sensitivity in Barrett's esophagus.
        J Clin Gastroenterol. 1987; 9: 23-27
        • Grade A
        • Pulliam G
        • Johnson C
        • Garewal H
        • Sampliner RE
        • Fass R
        Reduced chemoreceptor sensitivity in patients with Barrett's esophagus may be related to age and not to the presence of Barrett's epithelium.
        Am J Gastroenterol. 1997; 92: 2040-2043
        • Brandt LJ
        • Kauvar DR
        Laser-induced transient regression of Barrett's epithelium.
        Gastrointest Endosc. 1992; 38: 619-622
        • Van Laethem JL
        • Cremer M
        • Peny MO
        • Delhaye M
        • Deviere J
        Eradication of Barrett's mucosa with argon plasma coagulation and acid suppression: immediate and mid term results.
        Gut. 1998; 43: 747-751
        • Haag S
        • Nandurkar S
        • Talley NJ
        Regression of Barrett's esophagus: the role of acid suppression, surgery, and ablative methods.
        Gastrointest Endosc. 1999; 50: 229-240
        • Vaezi MF
        • Richter JE
        Role of acid and duodenogastroesophageal reflux in gastroesophageal reflux disease.
        Gastroenterology. 1996; 111: 1192-1199
        • Gillen P
        • Keeling P
        • Byrne PJ
        • Healy M
        • O'Moore RR
        • Hennessy TP
        Implication of duodenogastric reflux in the pathogenesis of Barrett's oesophagus.
        Br J Surg. 1988; 75: 540-543
        • Attwood SE
        • DeMeester TR
        • Bremner CG
        • Barlow AP
        • Hinder RA
        Alkaline gastroesophageal reflux: implications in the development of complications in Barrett's columnar-lined lower esophagus.
        Surgery. 1989; 106: 764-770
        • Shields HM
        • Zwas F
        • Antonioli DA
        • Doos WG
        • Kim S
        • Spechler SJ
        Detection by scanning electron microscopy of a distinctive esophageal surface cell at the junction of squamous and Barrett's epithelium.
        Dig Dis Sci. 1993; 38: 97-108
        • Boch JA
        • Shields HM
        • Antonioli DA
        • Zwas F
        • Sawhney RA
        • Trier JS
        Distribution of cytokeratin markers in Barrett's specialized columnar epithelium.
        Gastroenterology. 1997; 112: 760-765
        • O'Connor HJ
        Review article: Helicobacter pylori and gastrooesophageal reflux disease-clinical implications and management.
        Aliment Pharmacol Ther. 1999; 13: 117-127
        • O'Connor JB
        • Falk GW
        • Richter JE
        The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry.
        Am J Gastroenterol. 1999; 94: 2037-2042
        • El-Serag HB
        • Sonnenberg A
        Opposing time trends of peptic ulcer and reflux disease.
        Gut. 1998; 43: 327-333
        • Banatvala N
        • Mayo K
        • Megraud F
        • Jennings R
        • Deeks JJ
        • Feldman RA
        The cohort effect and Helicobacter pylori.
        J Infect Dis. 1993; 168: 219-221
        • Varanasi RV
        • Fantry GT
        • Wilson KT
        Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease.
        Helicobacter. 1998; 3: 188-194
        • Vicari JJ
        • Peek RM
        • Falk GW
        • et al.
        The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease.
        Gastroenterology. 1998; 115: 50-57
        • Werdmuller BF
        • Loffeld RJ
        Helicobacter pylori infection has no role in the pathogenesis of reflux esophagitis.
        Dig Dis Sci. 1997; 42: 103-105
        • El-Serag HB
        • Sonnenberg A
        • Jamal MM
        • Inadomi JM
        • Crooks LA
        • Feddersen RM
        Corpus gastritis is protective against reflux oesophagitis.
        Gut. 1999; 45: 181-185
        • Chow WH
        • Blaser MJ
        • Blot WJ
        • et al.
        An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma.
        Cancer Res. 1998; 58: 588-590
        • Richter JE
        • Falk GW
        • Vaezi MF
        Helicobacter pylori and gastroesophageal reflux disease: the bug may not be all bad.
        Am J Gastroenterol. 1998; 93: 1800-1802