Featuring 8 papers from a symposium on achalasia conducted by Drs. Marco Patti and Tim Farrell at the University of North Carolina. The essayists are all distinguished leaders in their field and our journal is honored to include the papers as a group.
Symposium
Esophageal Achalasia: Pathophysiology, Clinical Presentation, and Diagnostic Evaluation FRANCISCO SCHLOTTMANN, M.D.,* RAFAEL M. L. NETO, M.D.,† FERNANDO A. M. HERBELLA, M.D.,† MARCO G. PATTI, M.D.*
From the *Department of Medicine and Surgery, University of North Carolina, Chapel Hill, North Carolina and †Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil Esophageal achalasia is a primary esophageal motility disorder characterized by the absence of esophageal peristalsis and failure of the lower esophageal sphincter to relax in response to swallowing. These abnormalities lead to impaired emptying of food from the esophagus into the stomach with resulting food stasis. Most patients experience severe dysphagia, and regurgitation can lead to aspiration and respiratory problems. Consequently, the quality of life of patients affected by achalasia is severely impacted. A thorough evaluation with upper endoscopy, barium swallow, and esophageal manometry is mandatory to establish the diagnosis and plan the optimal treatment. In selected patients, an ambulatory pH monitoring is recommended to distinguish between gastroesophageal reflux disease and achalasia.
a primary esophageal motility disorder characterized by the absence of E esophageal peristalsis and failure of the lower esophaSOPHAGEAL ACHALASIA IS
geal sphincter (LES) to relax in response to swallowing. This disease is rare, with an incidence of about one in 100,000 individuals. Achalasia occurs with equal frequency in men and women and in white and nonwhite people, but incidence increases with age. In most studies, the mean age at diagnosis is over 50 years.1 Achalasia usually presents with symptoms of dysphagia, regurgitation of undigested food, respiratory symptoms (e.g. nocturnal cough or recurrent aspiration), chest pain, and weight loss. Similar clinical presentation; however, can occur in patients with pseudoachalasia (5% of patients with suspected achalasia) due to malignant obstruction or operations at the esophagogastric junction.2, 3 Achalasia can also be secondary to a tropical disease called Chagas’ disease, characterized by degeneration of the myenteric plexus due to Trypanosoma Cruzi infection.4 Although the etiology is still elusive, achalasia pathophysiology, diagnosis and treatment are well understood. Address correspondence and reprint requests to Francisco Schlottmann, University of North Carolina at Chapel Hill, 4030 Burnett Womack Building, 101 Manning Drive, CB 7081, Chapel Hill, NC 27599-7081. E-mail:
[email protected].
The diagnosis of achalasia is suggested by clinical features and confirmed by further diagnostic tests, such as esophagogastroduodenoscopy (EGD), barium swallow, and esophageal manometry. Recent advances in diagnostic methods, including high-resolution manometry (HRM), might even help predicting the outcome or selecting more appropriate treatment modalities.5, 6 The aim of this study was to review the pathophysiology, clinical presentation, and current diagnosis of esophageal achalasia. Pathophysiology
Normally, the LES has myogenic tone and remains intrinsically contracted in the absence of neural input or hormones, to prevent reflux of gastric contents. The LES relaxes in response to swallowing and esophageal or gastric distension. This muscle is also under neurogenic control involving the myenteric plexus, which contain both excitatory (acetylcholine producing) and inhibitory (nitric oxide and vasoactive intestinal peptide producing) motor neurons. In contrast, the smooth muscle of the esophageal body lacks a demonstrable tone, likely owing to differences in contractile proteins and isoforms compared with smooth muscle of the LES.7 Unlike contraction in the skeletal muscles controlled by central sequential
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activation of motor neurons, primary peristalsis along the smooth muscle portion of the esophageal body (distal two thirds) is initiated by nonsequential simultaneous central activation, and is believed to be propagated largely by peripheral mechanisms to produce deglutive inhibition followed by excitation. There is an intrinsic gradient of decreasing cholinergic and increasing nitrergic innervation distally in the esophagus.8 The pathophysiology of achalasia involves the selective degeneration of inhibitory neurons of the esophageal myenteric plexus, which are needed for peristalsis of the smooth muscle of the esophageal body and relaxation of the tonic LES.9 The etiology of this degeneration process, however, remains largely unknown. Detailed examination of resection specimens has shown infiltration of cytotoxic lymphocytes expressing activation markers.10 Viruses, such as herpes simplex virus 1, varicella-zoster, and human papillomavirus have been implicated in initiating an inflammatory reaction.11, 12 The preference of herpes virus for squamous rather than columnar epithelium could explain predominant esophageal involvement in achalasia, although largely sparing the rest of the gastrointestinal tract. However, previous investigators have failed to detect such viruses in myotomy specimens from achalasia patients.13, 14 Thus, the inciting antigen remains unknown. An autoimmune etiology has also been suggested, with evidence of circulating autoantibodies and antibodies against myenteric neurons in the serum of achalasia patients.15, 16 There are also reported familial cases of achalasia, including a case report of siblings with coexistent Hirschprung’s disease.17, 18 Albeit extremely rare, such cases raise the possibility of a genetic basis of the disease.
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and may lead to aspiration. Aspiration can cause respiratory symptoms, such as cough, hoarseness, wheezing, and episodes of pneumonia.19 Heartburn is present in about 50 per cent of patients. It is due to stasis and fermentation of undigested food in the distal esophagus, rather than due to gastroesophageal reflux. Because heartburn is frequently reported, misdiagnosis of achalasia as gastroesophageal reflux disease (GERD) can occur, particularly in the early stages of the disease.20 Chest pain or discomfort, located in the xiphoid area, is experienced by nearly 40 per cent of patients with achalasia. It may mimic angina by location and character, but differs in not being aggravated by exercise and being exacerbated by eating.21 The cause of chest pain is still unknown. It has been suggested that esophageal distension or esophageal contractions of abnormally high amplitude or long duration maybe responsible for esophageal chest pain of esophageal origin.22 The Eckardt Score is the grading system most frequently used for the evaluation of symptoms and efficacy of achalasia treatment.23 It attributes points (0–3 points) for four symptoms of the disease (dysphagia, regurgitation, chest pain, and weight loss), and it ranges from 0 to 12 (Table 1). Diagnostic Evaluation
Since a diagnosis based on symptoms only is uncertain, a proper workup is necessary to establish the diagnosis of achalasia. The diagnostic workup includes the following: EGD, barium swallow, esophageal manometry, and sometimes ambulatory 24-hour pH monitoring. EGD
Clinical Presentation
Dysphagia, for solids and liquids, is the most common symptom, occurring in over 90 per cent of patients. Some patients adapt to this symptom by changing their diet, and are able to maintain a stable weight, whereas others experience a progressive increase in dysphagia that eventually leads to weight loss.19 Regurgitation of undigested food is the second most frequent symptom and is present in about 75 per cent of patients. It occurs more often in the supine position,
This study is usually the first test performed in patients with dysphagia to rule out the presence of a mechanical obstruction secondary to a peptic stricture or cancer. An infiltrating tumor of the gastroesophageal junction can mimic the clinical, radiological, and manometric findings of achalasia, resulting in impaired LES relaxation, esophageal dilatation, and absence of peristalsis. This condition, defined as “secondary achalasia” or “pseudoachalasia,” should be suspected in patients older than
TABLE 1. Clinical Scoring System for Achalasia (Eckardt Score) Score
Weight Loss (kg)
Dysphagia
Retrosternal Pain
Regurgitation
0 1 2 3
None 10
None Occasional Daily Each meal
None Occasional Daily Each meal
None Occasional Daily Each meal
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60-years-old, with rapidly progressing dysphagia, excessive weight loss or both.24 The endoscopic findings in achalasia patients widely range from a normal exam (in about 40% of patients) to a tortuous and dilated esophagus with food retention.25 Some resistance to trespass the cardia may be noticed. The esophageal mucosa can be normal or can present signs of esophagitis with friability, thickening, and even erosions secondary to food stasis or Candida infection.26 Barium Swallow
This test provides information regarding the anatomy of the esophagus (diameter and axis) and associated conditions, such as epiphrenic diverticula or cancer. Typical radiological findings are a narrowing at the level of the gastroesophageal junction in a “bird beak” configuration with proximal dilatation of the esophagus, air-fluid levels, and absence of intra-gastric air (Fig. 1). In more advanced cases, severe dilatation with stasis of food and a sigmoid-like appearance can occur (Fig. 2). A timed barium swallow can be also performed to assess the emptying of the esophagus, by measuring the height of the barium column five minutes after ingestion of diluted barium.27
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The barium swallow, however, may show no abnormalities in about 30 per cent of the patients, particularly in the early stages of the disease. The expertise of the radiologist with this rare disease is key for a proper interpretation of the radiologic features. Esophageal Manometry
Esophageal manometry is the gold standard for the diagnosis of achalasia. Lack of peristalsis and absent or incomplete LES relaxation in response to swallowing are the main criteria for the diagnosis. The LES is hypertensive in about 50 per cent of patients.28 The introduction of HRM has improved the ability to diagnose achalasia and identify newer variants. As compared with conventional manometry, HRM determines more comfort and speediness to the test, easiness to teach, inter-observer and intra-observer reproducibility, and compensation of movements artifacts.29, 30 Briefly, HRM is performed after an overnight fast using a solid-state catheter with 36 circumferential sensors spaced at 1-cm intervals. The probe is inserted transnasally, and positioned to record from the pharynx to the stomach. Pressure,
FIG. 1. Barium swallow of an achalasia patient. “Bird beak” narrowing at the level of the gastroesophageal junction.
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length, and relaxation of the LES and the pressure of the upper esophageal sphincter are measured. Esophageal body motility is assessed starting with a basal period without swallowing, followed by 10 wet swallows of 5 mL of water at 30-second intervals. Amplitude, duration, and velocity of the peristaltic waves are recorded. HRM included new parameters, which led to a compilation of significant clinical findings under the
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Chicago classification.31, 32 This new classification includes three subtypes of achalasia (Fig. 3). Type I: incomplete LES relaxation, aperistalsis, and absence of esophageal pressurization. Type II: incomplete LES relaxation, aperistalsis, and panesophageal pressurization in at least 20 per cent of swallows. Type III: incomplete LES relaxation and premature contractions in at least 20 per cent of swallows (“spastic achalasia”) Subclassification of achalasia in types I, II, and III seems to be useful to predict outcomes. Pandolfino et al.33 reported that type II achalasia patients were significantly more likely to respond to laparoscopic Heller myotomy (LHM) (100%), as compared with type I (56% overall) and type III (29% overall). Concordantly, Salvador et al.34 evaluated 246 consecutive patients who underwent LHM and found that treatment failure rates were significantly different among the subtypes of achalasia: type I 14.6 per cent, type II 4.7 per cent, and type III 30.4 per cent (P 4 0.0007). A recent meta-analysis encompassing nine studies and 727 patients also showed that type II achalasia was associated with the best prognosis after pneumatic dilatation and LHM, whereas type III achalasia had the worst prognosis.35 The selection of the best initial approach for achalasia also appears to be influenced by the Chicago Classification. Although in types I and II achalasia, pneumatic dilatation and LHM appear to be the best optimal treatment, type III achalasia seems to be better managed with per oral endoscopic myotomy, probably because of the ability to do a longer myotomy of the thoracic esophagus.36, 37 Ambulatory 24-Hour pH Monitoring
FIG. 2. Barium swallow of an advanced-stage achalasia patient with dilated and sigmoid esophagus.
This test is recommended in selected patients when the diagnosis is uncertain, to distinguish between GERD and achalasia. The study is performed after
FIG. 3. Chicago classification of esophageal achalasia. Type I: Absence of esophageal pressurization; type II: Panesophageal pressurization; type III: Premature contractions.
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discontinuing acid-suppression medications 10 days (proton pump inhibitors) or three days (histamine-2 receptor antagonists) before the study. The dualchannel pH catheter with two sensors located 15 cm apart is placed transnasally so that the distal and the proximal sensors are positioned 5 and 20 cm above the upper border of the manometrically determined LES. Gastroesophageal reflux is evaluated in terms of the number of reflux episodes and amount of acid exposure (pH < 4). The examination of the pH-monitoring tracing is mandatory. In both GERD and achalasia, the test can be abnormal, but the tracing is different. Although in GERD patients the tracing is characterized by intermittent drops of pH below 4 with subsequent return of the pH values above 5, in achalasia patients there is a slow and progressive drift of the pH below 4 with no return to higher values (pseudo-GERD due to food fermentation).38 Conclusions
Esophageal achalasia is a rare disease characterized by the absence of esophageal peristalsis and failure of the LES to relax in response to swallowing. Dysphagia, regurgitation, heartburn, and chest pain are the most frequent symptoms in achalasia patients. A thorough evaluation with EGD, barium swallow, and esophageal manometry is mandatory to establish the diagnosis and plan the optimal treatment. In selected patients, an ambulatory pH monitoring is recommended to distinguish between GERD and achalasia. REFERENCES
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30. Herbella FA, Armijo PR, Patti MG. A pictorial presentation of 3.0 Chicago classification for esophageal motility disorders. Einstein (Sao Paulo) 2016;14:439–42. 31. Kahrilas PJ, Ghosh SK, Pandolfino JE. Esophageal motility disorders in terms of pressure topography: the Chicago classification. J Clin Gastroenterol 2008;42:627–35. 32. Kahrilas PJ, Bredenoord AJ, Fox M, et al. The Chicago classification of esophageal motility disorders, v3.0. Neuro Gastroenterol Motil 2015;27:160–74. 33. Pandolfino JE, Kwiatek MA, Nealis T, et al. Achalasia: a new clinically relevant classification by high-resolution manometry. Gastroenterology 2008;135:1526–33. 34. Salvador R, Costantini M, Zaninotto G, et al. The preoperative manometric pattern predicts the outcome of surgical treatment for esophageal achalasia. J Gastrointest Surg 2010;14:1635–45.
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35. Ou YH, Nie XM, Li LF, et al. High-resolution manometric subtypes as a predictive factor for the treatment of achalasia: a meta-analysis and systematic review. J Dig Dis 2016;17:222–35. 36. Kumbhari V, Tieu AH, Onimaru M, et al. Peroral endoscopic myotomy (POEM) vs laparoscopic Heller myotomy (LHM) for the treatment of type III achalasia in 75 patients: a multicenter comparative study. Endosc Int Open 2015;3:E195–201. 37. Khashab MA, Messallam AA, Onimaru M, et al. International multicenter experience with peroral endoscopic myotomy for the treatment of spastic esophageal disorders refractory to medical therapy (with video). Gastrointest Endosc 2015;81: 1170–7. 38. Patti MG, Arcerito M, Tong J, et al. Importance of preoperative and postoperative pH monitoring in patients with esophageal achalasia. J Gastrointest Surg 1997;1:505–10.
