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Pathogenesis of esophageal rings in eosinophilic esophagitis
Medical Hypotheses (2005) 64, 520–523
http://intl.elsevierhealth.com/journals/mehy
Pathogenesis of esophageal rings in eosinophilic esophagitis N.S. Mann*, J.W. Leung V.A. Medical Center, 150 Muir Road, Martinez, CA 94553, USA School of Medicine, University of California, Davis, CA, USA Received 22 July 2004; accepted 13 August 2004
Summary Eosinophilic esophagitis and eosinophilic gastroenteritis is being recognized more frequently among the adult patients. The disease is characterized by massive infiltration of the wall of gastrointestinal tract by sheets of eosinophils. The clinical features depend upon the site of involvement. They include dyspepsia, dysphagia, nausea, vomiting, chest pain, diarrhea and protein-losing enteropathy. Eosinophilic esophagitis may present as chest pain, dysphagia or dyspepsia. The characteristic endoscopic feature of eosinophilic esophagitis is the formation of fine concentric mucosal rings (corrugated esophagus). Regarding the pathogenesis of these mucosal rings our hypothesis is that mast cells in the esophageal wall in response to allergens release histamine, eosinophilic chemotactic factor and platelet activating factor, etc. which activate eosinophils to release toxic cationic proteins. Activation of acetyl choline by histamine may cause contraction of the muscle fibers in the muscularis mucosae resulting in the formation of esophageal rings. This hypothesis can be tested by demonstrating the contraction of muscle layers of muscularis mucosae with the use of high frequency endoscopic ultrasonic probe introduced via the biopsy channel of an endoscope. c 2004 Elsevier Ltd. All rights reserved.
Introduction Eosinophilic gastroenteritis may involve any part of the gastrointestinal tract from the esophagus to the rectum and is characterized by tissue eosinophilia [1,2]. It is an uncommon disease but more cases are being recognized now [1–4]. Peripheral blood eosinophilia may not be present and is no longer considered a diagnostic criterion for this disease [2]. The diagnostic criteria include the presence of gastrointestinal symptoms, presence of *
Corresponding author. Tel.: +1 925 370 4176; fax: +1 925 372 2185. E-mail address: [email protected] (N.S. Mann).
eosinophilic infiltrates in any segment of the gastrointestinal tract, absence of eosinophilic infiltrations in multiple organs outside the gut (which is a characteristic of hypereosinophilic syndrome) and absence of parasitic infestation, and other known causes of tissue eosinophilia. Eosinophilic infiltration of the gastrointestinal tract can occur after the use of cyclosporine [5], toxic oil syndrome [6], eosinophilic myalgia syndrome [7], immunodeficiency virus disease [8], connective tissue diseases or vasculitis, systemic mastocytosis, Crohn’s disease, celiac sprue, malignancy and milk protein sensitivity [9]. A few eosinophils are found in the wall of the GI tract in any inflammatory condition e.g. Crohn’s
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.08.021
Esophageal rings in eosinophilic esophagitis disease, ulcerative colitis, reflux esophagitis, etc., however, by histologic criteria, to qualify for the diagnosis of eosinophilic gastro-enteritis, massive infiltration with sheets of eosinophils is required. Although, the esophagus and colon can be involved but most commonly the stomach or small bowel is the site affected [9]. Rarely, hepatic granulomas infiltrated with eosinophils, eosinophilic cholecystitis, eosinophilic cholangitis and eosinophilic cystitis are associated with eosinophilic gastroenteritis [9]. The clinical features may be intermittent but may be of long duration; in some cases the disease is self-limited and may not require any treatment [9]. Peripheral eosinophilia may be present in 80% of the cases; highest eosinophil counts occur in patients with predominantly serosal involvement which may be associated with eosinophilic ascites [9]. Iron-deficiency anemia, protein-losing enteropathy and steatorrhea may be present [9]. Gastric outlet obstruction either due to mechanical obstruction secondary to eosinophilic polypoid masses in the pylorus or gastric motility disorder may be present. Symptoms may include colicky abdominal pain, nausea, vomiting, diarrhea, weight loss, and dyspepsia. With esophageal involvement chest pain, nausea and dysphagia may occur. Acute pancreatitis due to mucosal swelling in the region of the ampulla of Vater has been described [10]. Severe protein loss may result in low immunoglobulin levels but serum IgE levels may be elevated if there is history of food allergy particularly in children.
Pathogenesis Recent evidence suggests that eosinophils may directly damage the gut mucosa and gut wall. Eosinophil granules contain cationic proteins such as major basic protein, eosinophil derived neurotoxin, eosinophilic cationic protein and eosinophil peroxidase [11–13]. These cationic proteins may destroy tissues directly or through the synthesis of leukotrienes [14]. Eosinophils also contain interleukin-3 and -5, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha which may promote tissue inflammation. In sensitized people, IgE interacting with food allergens and other allergens may degranulate mast cells releasing histamine, platelet activating factor, leukotriene B4 and eosinophil chemotactic factor; the latter attracts and recruits more eosinophils to the affected site. The activated eosinophils release toxic cationic proteins which cause tissue damage and also
521 cause further degranulation of mast cells releasing histamine and other factors listed above. Thus, a vicious cycle is induced. The management of eosinophilic gastroenteritis includes diet modification, sodium cromoglycate, glucocorticoids, immunosuppressive agents [9] and Ketotifen, an H1-antihistamine [15]. Gastric outlet obstruction, small bowel obstruction, gastro-intestinal bleeding or perforation may require surgical intervention.
Eosinophilic esophagitis The esophageal wall like the rest of the gut wall consists of the following layers: (1) epithelium; (2) lamina propria which consists of compact connective tissue and elastic fibers; (3) muscularis mucosae which consists of a plexus of non-striated muscle fibers which can alter the configuration of the mucosa by contraction of its inner circular and outer longitudinal layers. These three layers constitute the mucosa; (4) submucosa is rich in nerves, lymphatics and blood vessels; (5) muscularis externa is the main muscle coat consisting of an inner circular and outer longitudinal muscle layers; (6) adventitia which consists of dense connective tissue; in the rest of the gut, instead of adventitia there is serosa and parietal peritoneum. There are three neural plexuses in the esophageal wall: one between the circular and longitudinal muscle layers of the muscularis externa; another in the submucosa and the third associated with muscularis mucosae. Like in the rest of the gut wall, eosinophilic infiltration in the esophagus may be present in the mucosa, muscle layer and serosal layer; of these rarest forms is the serosal disease. At one time eosinophilic esophagitis was considered to be mainly a disease of infants and young children but now cases in adults are being increasingly recognized [16–18]. The symptoms of eosinophilic esophagitis include post prandial nausea, dyspepsia chest pain, and early satiety. In adults it may present as dysphagia and food impaction. In children elimination of offending food for 8–10 weeks may resolve the problem. If the offending allergen is not found then treatment with glucocorticoids may be effective. On endoscopy the characteristic finding is the presence of multiple mucosal rings (corrugated esophagus or felinization of the esophagus) and esophageal stenosis has been seen [16–19]. Endoscopic biopsy shows extensive infiltration with eosinophils of the esophageal wall. When the eosi-
522 nophilic infiltration is limited to the mucosa, then there is no abnormality of esophageal motility. However, when the esophageal muscle layer is infiltrated with eosinophils, then esophageal dysmotility may be present [20]. In patients with ringed esophagus, when an attempt is made to dilate the esophagus, significant mucosal tears may occur and only limited dilatation can be achieved because of the rigidity of the esophageal wall [17,18].
Hypothesis about pathogenesis of mucosal rings As already mentioned, degranulation of the mast cells by IgE mediated allergic reaction results in the release of histamine, eosinophilic chemotactic factor, platelet activating factor, etc. which activate eosinophils to release toxic cationic proteins. Histamine may activate acetyl choline which will contract the muscle layers in the muscularis mucosae; contraction of the muscle fibers in the musculasis mucosae will deform the mucosal layer resulting in the formation of esophageal rings. Initially these rings may be transient and reversible. However, with continuous contraction of the muscle fibers, hypertrophy and thickening of the muscle layers of the muscular mucosae becomes permanent. This may explain the rigidity of the mucosa and submucosa in these patients resulting in mucosal tears and a greater risk of esophageal perforation when esophageal dilation is attempted. If treated early with antihistamine H1 blockers, such as ketotifen [15], permanent muscular thickening of the muscularis mucosa can be prevented and many symptoms of eosinophilic esophagitis may be ameliorated.
Testing the hypothesis It is possible to evaluate the state and thickening of the various layers of the esophagus by performing endoscopic ultrasound using a 2 mm ultrasonic probe introduced via the biopsy channel of the endoscope [21,22]. It is a high frequency ultrasonic probe. By this technique contraction and thickening of the muscles of the muscularis mucosae in the area of esophageal mucosal rings can be demonstrated. Also by this technique effect of H1-blocking antihistamines such as ketotifen on these muscle layers can be
Mann and Leung documented. It is possible that chest pain which occurs in patients with eosinophilic esophagitis is due to spasm of the muscular layer of muscularis mucosae.
Acknowledgement We are thankful to Frances Hill for excellent secretarial support.
References [1] Cello JP. Eosinophilic gastroenteritis – a complex disease. Am J Med 1979;67:1097–104. [2] Talley NJ, Shorter RG, Phillips SF. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosae, muscle layer and subserosal tissues. Gut 1990;31:54–61. [3] Blackshaw AJ, Levison DA. Eosinophilic infiltrates of the gastrointestinal tract. J Clin Pathol 1986;39:1–8. [4] Naylor AR. Eosinophilic gastroenteritis. Scot Med J 1990;35:163–7. [5] Dhawan A, Seemayer TA, Pinsinski C. Post transplant eosinophilic gastroenteritis in children. Liver Transpl Surg 1997;3:591–5. [6] Killbourne EM, Rigau-Perez JG, Heath CW. Clinical epidemiology of toxic oil syndrome: manifestations of a new illness. N Engl J Med 1983;309:1408–14. [7] Hertzman PA, Blevias WL, Mayer J. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:869–74. [8] Mazza DS, O’Sullivan M, Grieco MH. HIV-1 infection complicated by food allergy and allergic gastroenteritis. Ann Allergy 1991;66:436–9. [9] Talley NJ. In: Feldman, Friedman, Sleisenger, editors. Eosinophilic gastroenteritis in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. Philadelphia: W.B. Saunders. p.1972–80. [10] Maeshima A, Murakami H, Sadakata H. Eosinophilic gastroenteritis presenting with acute pancreatitis. J Med 1997;28:265–7. [11] Altman LC, Gleich GJ. Eosinophils Immunol Aller Clin North Am 1990;10:263–74. [12] Weller PF. The immunobiology of eosinophils. N Engl J Med 1991;324:110–21. [13] Gleich GJ, Adolphson CR. The eosinophilic leukocyte: structure and function. Adv Immunol 1986;39:177–89. [14] Shaw RJ, Walsh GM, Cromwell O. Activated human eosinophils generate SRS-A leukotrienes following IgG-dependent stimulation. Nature 1985;316:150–5. [15] Melamed I, Feanny SF, Sherman PM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310–5. [16] Katzka DA, Levin MS, Ginsberg GG, Hammond R, Katz PO, Insko EK et al. Congenital esophageal stenosis in adults. Am J Gastro 2000;95:32–6. [17] Langdon DE. Congenital esophageal stenosis, corrugated ringed esophagus and eosinophilic esophagitis. Am J Gastroenterol 2000;95:2123–4.
Esophageal rings in eosinophilic esophagitis [18] Langdon DE. Corrugated ringed esophagus and too small esophagi. Am J Gastroenterol 1999;94:542–3. [19] Bousvaros A, Antonioli DA, Winter HS. Ringed esophagus: An association with esophagitis. Am J Gastroenterol 1992;87:1187–90. [20] Landers RT, Kuster GGR, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 1978;74:1298–301.
523 [21] Pehlivanov N, Jianmin L, Mittal R. Identification of different patterns of pressure waves in achalasia of the esophagus by high frequency intraluminal probe sonography. Gastroenterology 2002;122:A341–M1716. [22] Feria M, Liu J, Mittal R. Dissociation between the duration of circular and longitudinal muscle contraction in patients with diffuse esophageal spasm. Gastroenterology 2002;122:A341–M1714.
http://intl.elsevierhealth.com/journals/mehy
Pathogenesis of esophageal rings in eosinophilic esophagitis N.S. Mann*, J.W. Leung V.A. Medical Center, 150 Muir Road, Martinez, CA 94553, USA School of Medicine, University of California, Davis, CA, USA Received 22 July 2004; accepted 13 August 2004
Summary Eosinophilic esophagitis and eosinophilic gastroenteritis is being recognized more frequently among the adult patients. The disease is characterized by massive infiltration of the wall of gastrointestinal tract by sheets of eosinophils. The clinical features depend upon the site of involvement. They include dyspepsia, dysphagia, nausea, vomiting, chest pain, diarrhea and protein-losing enteropathy. Eosinophilic esophagitis may present as chest pain, dysphagia or dyspepsia. The characteristic endoscopic feature of eosinophilic esophagitis is the formation of fine concentric mucosal rings (corrugated esophagus). Regarding the pathogenesis of these mucosal rings our hypothesis is that mast cells in the esophageal wall in response to allergens release histamine, eosinophilic chemotactic factor and platelet activating factor, etc. which activate eosinophils to release toxic cationic proteins. Activation of acetyl choline by histamine may cause contraction of the muscle fibers in the muscularis mucosae resulting in the formation of esophageal rings. This hypothesis can be tested by demonstrating the contraction of muscle layers of muscularis mucosae with the use of high frequency endoscopic ultrasonic probe introduced via the biopsy channel of an endoscope. c 2004 Elsevier Ltd. All rights reserved.
Introduction Eosinophilic gastroenteritis may involve any part of the gastrointestinal tract from the esophagus to the rectum and is characterized by tissue eosinophilia [1,2]. It is an uncommon disease but more cases are being recognized now [1–4]. Peripheral blood eosinophilia may not be present and is no longer considered a diagnostic criterion for this disease [2]. The diagnostic criteria include the presence of gastrointestinal symptoms, presence of *
Corresponding author. Tel.: +1 925 370 4176; fax: +1 925 372 2185. E-mail address: [email protected] (N.S. Mann).
eosinophilic infiltrates in any segment of the gastrointestinal tract, absence of eosinophilic infiltrations in multiple organs outside the gut (which is a characteristic of hypereosinophilic syndrome) and absence of parasitic infestation, and other known causes of tissue eosinophilia. Eosinophilic infiltration of the gastrointestinal tract can occur after the use of cyclosporine [5], toxic oil syndrome [6], eosinophilic myalgia syndrome [7], immunodeficiency virus disease [8], connective tissue diseases or vasculitis, systemic mastocytosis, Crohn’s disease, celiac sprue, malignancy and milk protein sensitivity [9]. A few eosinophils are found in the wall of the GI tract in any inflammatory condition e.g. Crohn’s
0306-9877/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2004.08.021
Esophageal rings in eosinophilic esophagitis disease, ulcerative colitis, reflux esophagitis, etc., however, by histologic criteria, to qualify for the diagnosis of eosinophilic gastro-enteritis, massive infiltration with sheets of eosinophils is required. Although, the esophagus and colon can be involved but most commonly the stomach or small bowel is the site affected [9]. Rarely, hepatic granulomas infiltrated with eosinophils, eosinophilic cholecystitis, eosinophilic cholangitis and eosinophilic cystitis are associated with eosinophilic gastroenteritis [9]. The clinical features may be intermittent but may be of long duration; in some cases the disease is self-limited and may not require any treatment [9]. Peripheral eosinophilia may be present in 80% of the cases; highest eosinophil counts occur in patients with predominantly serosal involvement which may be associated with eosinophilic ascites [9]. Iron-deficiency anemia, protein-losing enteropathy and steatorrhea may be present [9]. Gastric outlet obstruction either due to mechanical obstruction secondary to eosinophilic polypoid masses in the pylorus or gastric motility disorder may be present. Symptoms may include colicky abdominal pain, nausea, vomiting, diarrhea, weight loss, and dyspepsia. With esophageal involvement chest pain, nausea and dysphagia may occur. Acute pancreatitis due to mucosal swelling in the region of the ampulla of Vater has been described [10]. Severe protein loss may result in low immunoglobulin levels but serum IgE levels may be elevated if there is history of food allergy particularly in children.
Pathogenesis Recent evidence suggests that eosinophils may directly damage the gut mucosa and gut wall. Eosinophil granules contain cationic proteins such as major basic protein, eosinophil derived neurotoxin, eosinophilic cationic protein and eosinophil peroxidase [11–13]. These cationic proteins may destroy tissues directly or through the synthesis of leukotrienes [14]. Eosinophils also contain interleukin-3 and -5, granulocyte-macrophage colony stimulating factor and tumor necrosis factor-alpha which may promote tissue inflammation. In sensitized people, IgE interacting with food allergens and other allergens may degranulate mast cells releasing histamine, platelet activating factor, leukotriene B4 and eosinophil chemotactic factor; the latter attracts and recruits more eosinophils to the affected site. The activated eosinophils release toxic cationic proteins which cause tissue damage and also
521 cause further degranulation of mast cells releasing histamine and other factors listed above. Thus, a vicious cycle is induced. The management of eosinophilic gastroenteritis includes diet modification, sodium cromoglycate, glucocorticoids, immunosuppressive agents [9] and Ketotifen, an H1-antihistamine [15]. Gastric outlet obstruction, small bowel obstruction, gastro-intestinal bleeding or perforation may require surgical intervention.
Eosinophilic esophagitis The esophageal wall like the rest of the gut wall consists of the following layers: (1) epithelium; (2) lamina propria which consists of compact connective tissue and elastic fibers; (3) muscularis mucosae which consists of a plexus of non-striated muscle fibers which can alter the configuration of the mucosa by contraction of its inner circular and outer longitudinal layers. These three layers constitute the mucosa; (4) submucosa is rich in nerves, lymphatics and blood vessels; (5) muscularis externa is the main muscle coat consisting of an inner circular and outer longitudinal muscle layers; (6) adventitia which consists of dense connective tissue; in the rest of the gut, instead of adventitia there is serosa and parietal peritoneum. There are three neural plexuses in the esophageal wall: one between the circular and longitudinal muscle layers of the muscularis externa; another in the submucosa and the third associated with muscularis mucosae. Like in the rest of the gut wall, eosinophilic infiltration in the esophagus may be present in the mucosa, muscle layer and serosal layer; of these rarest forms is the serosal disease. At one time eosinophilic esophagitis was considered to be mainly a disease of infants and young children but now cases in adults are being increasingly recognized [16–18]. The symptoms of eosinophilic esophagitis include post prandial nausea, dyspepsia chest pain, and early satiety. In adults it may present as dysphagia and food impaction. In children elimination of offending food for 8–10 weeks may resolve the problem. If the offending allergen is not found then treatment with glucocorticoids may be effective. On endoscopy the characteristic finding is the presence of multiple mucosal rings (corrugated esophagus or felinization of the esophagus) and esophageal stenosis has been seen [16–19]. Endoscopic biopsy shows extensive infiltration with eosinophils of the esophageal wall. When the eosi-
522 nophilic infiltration is limited to the mucosa, then there is no abnormality of esophageal motility. However, when the esophageal muscle layer is infiltrated with eosinophils, then esophageal dysmotility may be present [20]. In patients with ringed esophagus, when an attempt is made to dilate the esophagus, significant mucosal tears may occur and only limited dilatation can be achieved because of the rigidity of the esophageal wall [17,18].
Hypothesis about pathogenesis of mucosal rings As already mentioned, degranulation of the mast cells by IgE mediated allergic reaction results in the release of histamine, eosinophilic chemotactic factor, platelet activating factor, etc. which activate eosinophils to release toxic cationic proteins. Histamine may activate acetyl choline which will contract the muscle layers in the muscularis mucosae; contraction of the muscle fibers in the musculasis mucosae will deform the mucosal layer resulting in the formation of esophageal rings. Initially these rings may be transient and reversible. However, with continuous contraction of the muscle fibers, hypertrophy and thickening of the muscle layers of the muscular mucosae becomes permanent. This may explain the rigidity of the mucosa and submucosa in these patients resulting in mucosal tears and a greater risk of esophageal perforation when esophageal dilation is attempted. If treated early with antihistamine H1 blockers, such as ketotifen [15], permanent muscular thickening of the muscularis mucosa can be prevented and many symptoms of eosinophilic esophagitis may be ameliorated.
Testing the hypothesis It is possible to evaluate the state and thickening of the various layers of the esophagus by performing endoscopic ultrasound using a 2 mm ultrasonic probe introduced via the biopsy channel of the endoscope [21,22]. It is a high frequency ultrasonic probe. By this technique contraction and thickening of the muscles of the muscularis mucosae in the area of esophageal mucosal rings can be demonstrated. Also by this technique effect of H1-blocking antihistamines such as ketotifen on these muscle layers can be
Mann and Leung documented. It is possible that chest pain which occurs in patients with eosinophilic esophagitis is due to spasm of the muscular layer of muscularis mucosae.
Acknowledgement We are thankful to Frances Hill for excellent secretarial support.
References [1] Cello JP. Eosinophilic gastroenteritis – a complex disease. Am J Med 1979;67:1097–104. [2] Talley NJ, Shorter RG, Phillips SF. Eosinophilic gastroenteritis: a clinicopathological study of patients with disease of the mucosae, muscle layer and subserosal tissues. Gut 1990;31:54–61. [3] Blackshaw AJ, Levison DA. Eosinophilic infiltrates of the gastrointestinal tract. J Clin Pathol 1986;39:1–8. [4] Naylor AR. Eosinophilic gastroenteritis. Scot Med J 1990;35:163–7. [5] Dhawan A, Seemayer TA, Pinsinski C. Post transplant eosinophilic gastroenteritis in children. Liver Transpl Surg 1997;3:591–5. [6] Killbourne EM, Rigau-Perez JG, Heath CW. Clinical epidemiology of toxic oil syndrome: manifestations of a new illness. N Engl J Med 1983;309:1408–14. [7] Hertzman PA, Blevias WL, Mayer J. Association of the eosinophilia-myalgia syndrome with the ingestion of tryptophan. N Engl J Med 1990;322:869–74. [8] Mazza DS, O’Sullivan M, Grieco MH. HIV-1 infection complicated by food allergy and allergic gastroenteritis. Ann Allergy 1991;66:436–9. [9] Talley NJ. In: Feldman, Friedman, Sleisenger, editors. Eosinophilic gastroenteritis in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. Philadelphia: W.B. Saunders. p.1972–80. [10] Maeshima A, Murakami H, Sadakata H. Eosinophilic gastroenteritis presenting with acute pancreatitis. J Med 1997;28:265–7. [11] Altman LC, Gleich GJ. Eosinophils Immunol Aller Clin North Am 1990;10:263–74. [12] Weller PF. The immunobiology of eosinophils. N Engl J Med 1991;324:110–21. [13] Gleich GJ, Adolphson CR. The eosinophilic leukocyte: structure and function. Adv Immunol 1986;39:177–89. [14] Shaw RJ, Walsh GM, Cromwell O. Activated human eosinophils generate SRS-A leukotrienes following IgG-dependent stimulation. Nature 1985;316:150–5. [15] Melamed I, Feanny SF, Sherman PM. Benefit of ketotifen in patients with eosinophilic gastroenteritis. Am J Med 1991;90:310–5. [16] Katzka DA, Levin MS, Ginsberg GG, Hammond R, Katz PO, Insko EK et al. Congenital esophageal stenosis in adults. Am J Gastro 2000;95:32–6. [17] Langdon DE. Congenital esophageal stenosis, corrugated ringed esophagus and eosinophilic esophagitis. Am J Gastroenterol 2000;95:2123–4.
Esophageal rings in eosinophilic esophagitis [18] Langdon DE. Corrugated ringed esophagus and too small esophagi. Am J Gastroenterol 1999;94:542–3. [19] Bousvaros A, Antonioli DA, Winter HS. Ringed esophagus: An association with esophagitis. Am J Gastroenterol 1992;87:1187–90. [20] Landers RT, Kuster GGR, Strum WB. Eosinophilic esophagitis in a patient with vigorous achalasia. Gastroenterology 1978;74:1298–301.
523 [21] Pehlivanov N, Jianmin L, Mittal R. Identification of different patterns of pressure waves in achalasia of the esophagus by high frequency intraluminal probe sonography. Gastroenterology 2002;122:A341–M1716. [22] Feria M, Liu J, Mittal R. Dissociation between the duration of circular and longitudinal muscle contraction in patients with diffuse esophageal spasm. Gastroenterology 2002;122:A341–M1714.