Achalasia and Esophageal Outlet Obstruction



Fig. 1.1
Schematic representation of etiology proposed to underlie the different achalasia phenotypes



Esophagogastric junction outflow obstruction (EGJOO) is a condition characterized by HRM findings of impaired EGJ function but, at least in part, preserved peristalsis. The diagnosis of EGJOO in case series appears to be increasingly common, likely due to increased availability of HRM in routine clinical practice. EGJOO has been referred to as variant achalasia; however, it can be caused not only by functional but also by structural pathology (Table 1.1). Functional causes include early-stage achalasia in which the nonrelaxing LES is not yet accompanied by severe motor disorders of the esophageal body (i.e., early achalasia). Structural causes include peptic stenosis (i.e., related to acid reflux), inflammation (e.g., eosinophilic esophagitis), previous surgery (e.g., after fundoplication), or neoplasia (often labeled “pseudoachalasia”). True paraneoplastic causes of achalasia caused by the destruction of inhibitory innervation by tumor antibodies from distant tumors (e.g., lung cancer) are much rarer than local invasion of the EGJ by tumor or external compression of the distal esophagus by metastases. A combination of endoscopy and imaging to exclude a structural cause is prudent before a diagnosis of EGJOO is made. A typical finding in functional causes (i.e., motility disorders) is increased wall thickness from muscle hypertrophy.


Table 1.1
Causes of esophagogastric junction outflow obstruction (EGJOO)























1. Structural pathology

 • Reflux-induced strictures, Schatzki’s ring

 • Hiatus hernia

 • Eosinophilic esophagitis

 • Malignancy (esophageal, cardia)

 • Extrinsic compression (malignancy)

 • Surgical (post-fundoplication/bariatric surgery)

2. Functional (no structural pathology)

 • Impaired LES relaxation (“variant achalasia”)



Diagnosis


The diagnosis of achalasia and EGJOO is suspected in patients who have long-standing dysphagia to solids and liquids with regurgitation of undigested material that can include saliva. A careful clinical history, followed by upper gastrointestinal endoscopy and appropriate radiological investigations to rule out structural lesions including underlying malignancy, is essential in the initial workup to exclude local pathology. Occult malignant infiltration of the gastroesophageal junction is a rare but important differential diagnosis that affects about 2% of patients evaluated for achalasia. These patients are generally older and have a more rapidly progressive clinical course [11].


Clinical Presentation


The annual incidence of achalasia is 1/100,000 and the prevalence is 10/100,000 [12]. Patients most commonly present between the ages of 25 and 60 years with no gender or racial preference. Dysphagia of both solids (91%) and liquids (85%) with regurgitation of saliva and undigested food (76–91%) is a frequent symptom in patients with achalasia [1318] (Table 1.2). Other presenting symptoms include slow eating, heartburn, chest pain, and respiratory symptoms including cough [15]. Achalasia can present with symptoms that suggest gastroesophageal reflux disease [1721] and up to 49% of patients were reported to experience heartburn in one series [20]. Heartburn can be caused by intermittent reflux with prolonged acid exposure due to impaired clearance; however, this nonspecific symptom can also be due to mechanical distension of the esophagus and chemical irritation of the mucosal lining by food or lactate production by bacterial fermentation of retained carbohydrate [18]. Chest pain is reported in 25–63% of patients and is thought to be common in Type III achalasia [22]. Up to 41% of patients in one study experienced supraesophageal symptoms [14]. Impaired clearance of esophageal contents predisposes patients to aspiration. Abnormal radiological findings of centrilobular nodules with “tree-in-bud” pattern, septal thickening, and necrotizing pneumonia are reported [23].


Table 1.2
Symptom patterns in patients with achalasia




























































Author

Dysphagia

Chest pain

Heartburn

Regurgitation

Others

Eckardt et al. [13]
 
64/101 (63%)
     

Sinan et al. [15]

95/110 (86%)

35/110 (32%)

45/110 (41%)

70/110 (63%)
 

Fisichella et al. [16]

136/145 (94%)

60/145 (41%)

75/145 (52%)

110/145 (76%)

Aspiration (18/145) 12%

Spechler et al. [18]

66/67 (99%)

35/67 (52%)

32/67 (48%)

47/67 (70%)
 

Ponce et al. [19]
   
15/40 (38%)
   

Huselmans et al. [21]

200/209 (96%)

53/209 (25%)

37/209 (18%)
 
Weight loss (82/209) 39%

The symptoms of EGJOO are similar to achalasia. Most of the patients present with dysphagia to solids, chest pain, and nonspecific reflux symptoms [2427] (Table 1.3). As EGJOO is a manometric diagnosis, a careful evaluation to exclude a structural cause is important. Patients with a structural cause of EGJOO tend to complain more of dysphagia (62% vs. 25%, p = 0.09) and chest pain (75% vs. 25%, p = 0.08) than those with functional EGJOO [26]. A short history, weight loss, and older age at presentation may clinically be suspicious of an underlying malignancy. Patients with EGJOO should undergo further evaluation to exclude neoplastic or inflammatory changes.


Table 1.3
Symptom patterns in patients with functional esophagogastric junction outflow obstruction (EGJOO)








































Author

Dysphagia

Chest pain

Heartburn/regurgitation

Others

Scherer et al. [24]

15/16 (94%)

4/16 (25%)

9/16 (56%)

Globus 3/16 (19%)

Van Hoeij et al. [25]

23/34 (68%)

24/34 (71%)

12/34 (35%)

Cough/globus/dyspepsia 5/34 (15%)

Perez-Fernandez et al. [26]

21/28 (75%)

13/28 (46%)

19/28 (68%)

Atypical GERD 10/28 (36%)

Dyspepsia (12/28) 43%

Clayton et al. [27]

24/27 (89%)

2/27 (7%)
 
Cough 1/27(4%)


Endoscopy


The role of upper gastrointestinal gastroscopy is to rule out a mechanical cause with particular emphasis on the EGJ and gastric cardia. Findings may range from a normal appearing esophagus to a dilated esophagus with retained food/saliva and in advanced cases a sigmoid esophagus. Investigation should always include biopsies of the distal and mid-esophagus to exclude eosinophilic esophagitis as a cause of swallowing difficulties. Biopsies will also rule out squamous mucosal dysplasia and Barrett esophagus that can be caused due to chronic inflammation. It should be emphasized that this investigation is poorly sensitive in the early stages of achalasia prior to the occurrence of esophageal dilatation.

Endoscopic ultrasound (EUS) is requested to exclude infiltrating tumor at the EGJ or external compression of the distal esophagus due to lymph node metastases or other neoplastic pathology. This is especially appropriate in patients with rapidly progressive symptoms or EGJOO in whom the etiology is uncertain. In addition, EUS serves an adjunctive role for the diagnosis of major motility disorders in which there is often evidence of thickening of the esophageal smooth muscle [28].


Barium Studies


The classic “bird’s-beak” appearance at the EGJ on barium swallow arises as a result of impaired emptying of barium, esophageal dilation, and minimal LES opening. However, these features occur only in more advanced cases of achalasia, barium studies, and lack of diagnostic sensitivity (60%). Radiology serves a useful adjunctive role to rule out structural lesions, estimate esophageal diameter, and assess for the presence of epiphrenic diverticula [29]. The timed barium esophagogram (TBE) provides a standardized assessment of esophageal clearance function and can be helpful to assess treatment effect (see below).


Manometry


The diagnosis of achalasia is established on manometry . Typical findings on conventional manometry with 5–8 pressure sensors including a sleeve sensor at the LES were the absence of peristalsis and incomplete relaxation of the LES during deglutition [30]. The current reference standard is high-resolution manometry (HRM) with up to 36 closely spaced pressure sensors [31]. HRM data is displayed as esophageal pressure topography (EPT) plots, also known as Clouse plots , a continuous representation of motility and function from the pharynx to the stomach [32]. Analysis of this data calculates metrics that provide an objective assessment of esophageal and EGJ/LES function. Based on these HRM metrics the Chicago Cassification provides a diagnosis of esophageal motility disorders. This stepwise, hierarchical algorithm places most emphasis on EGJ disorders (i.e., achalasia, EGJOO) since these have the greatest impact on bolus transport and symptoms [33]. HRM increases interobserver agreement [34] and diagnostic accuracy compared to conventional manometry [35] and provides definitive diagnosis.

The integrated relaxation pressure (IRP) is a metric that was developed to quantify EGJ relaxation and opening [36]. An electronic sleeve sensor compensates for any movement of the LES during respiration [37]. The IRP is calculated from the electronic sleeve as the mean value during 4 s of maximal EGJ relaxation after pharyngeal contraction. Validation studies have shown that this provides a more accurate diagnosis of achalasia than previous metrics based on conventional manometry (e.g., nadir LES pressure, percentage LES relaxation) [36, 37]. The diagnosis of achalasia is based on an elevated IRP > 15 mm Hg in the absence of peristaltic contractions in the esophageal body. The diagnosis of EGJOO also requires an elevated IRP > 15 mm Hg but with preserved esophageal contractility [2] (Fig. 1.2).

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Fig. 1.2
HRM findings in achalasia and EGJOO. HRM findings relevant to the Chicago Classification are highlighted by application of a 30 mm Hg isobaric contour plot (black). The condition is diagnosed by the presence of impaired EGJ relaxation as defined by raised IRP > 15 mm Hg. (a) Type I achalasia: elevated IRP with absent peristalsis and minimal contractile activity between the upper esophageal sphincter and EGJ junction. (b) Type II achalasia: elevated IRP with pan-esophageal pressurization to ≥30 mm Hg in ≥20% of wet swallows. Note also significant esophageal shortening (swallow #10). This can lead to false-negative diagnosis due to “pseudo-relaxation” (movement of LES above sleeve sensor) in patients with conventional manometry even in the presence of a sleeve sensor [123]. (c) Type III achalasia: elevated IRP with ≥20% of wet swallows associated with spastic (premature) contractions. Note esophageal shortening during spasm. (d) EGJOO: elevated IRP with ≥20% of wet swallows associated with compartmentalized pressurization between peristaltic contractions and the EGJ. Repeat endoscopy to reassess the local anatomy showed no obvious inflammation; however, biopsies from the mid- and distal esophagus revealed eosinophilic esophagitis

Three subtypes of achalasia have been described [37] based on the presence of raised IRP and the pattern of contractility in the esophageal body during HRM studies: Type I “classic” achalasia (without evidence of pressurization or contractility); Type II achalasia (with pan-esophageal pressurization); and Type III “vigorous” achalasia (with ≥2 spastic contractions in the distal esophagus). This classification is clinically relevant since the subtype of achalasia guides treatment decisions and predicts outcome (Fig. 1.2a, b, and c).

The Chicago Classification identifies esophagogastric junction outflow obstruction (EGJOO) as a major motility disorder [33]. The diagnosis is applied to any pathological process, whether functional or structural, that affects esophageal transit across the EGJ in which effective peristaltic contractions are observed. It is the presence of effective esophageal body peristalsis that distinguishes EGJOO from achalasia (Fig. 1.2d). There are diverse structural and functional causes of EGJOO (Table 1.1).


HRM with Adjunctive Tests/Physiological Challenge


The current Chicago Classification is based on the analysis of ten 5 mL water swallows in the supine position. This approach is nonphysiological as eating and drinking is a continuous process performed in the upright position. Studies have shown that, also in healthy volunteers, multiple swallows are often necessary to clear a solid bolus as not every single swallow is effective [38, 39]. In addition, esophageal symptoms almost never occur with water swallows but during normal eating and drinking [40].

Adjunctive tests with rapid drink challenge (RDC; 100–200 mL water) and/or a solid test meal may improve diagnostic sensitivity (Fig. 1.3d) [41, 42]. In particular, EGJOO may not be evident with water swallows because the resistance to bolus passage is minimal. Increasing the physiological load by increasing fluid volume or bolus viscosity can highlight functional or structural obstruction to bolus transport. For example, whereas most patients show a decreased IRP during repeated swallowing due to profound EGJ relaxation, patients with achalasia showed a higher IRP during 200 mL RDC (Fig. 1.3a, b, and c) [41]. Similarly application of HRM with a standardized test meal highlights EGJ obstruction in patients with persistent dysphagia after fundoplication (Fig. 1.3d) [43]. This finding identified patients that responded to pneumatic dilatation of the EGJ in whom other investigations were nondiagnostic. In the future the use of concurrent, high-resolution intraluminal impedance with HRM will clarify the impact of motility on esophageal function. The combined technique highlights the presence of food and fluid (and gas) in the esophagus. This is important as, in most cases, it is not motility disorders per se but bolus retention that leads to symptoms.

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Fig. 1.3
Use of adjunctive tests with HRM in investigation of achalasia and EGJOO. (a) Example of a single water swallow (SWS) followed by rapid drink challenge (RDC) in normal subject. There is complete esophagogastric junction (EGJ) relaxation and suppression of contractility during RDC. IRP is lower during RDC than SWS (6 mm Hg vs. mean 9 mm Hg). RDC is followed by an effective clearance contraction. (b) Typical findings of SWS and RDC in achalasia. SWS is associated with aperistalsis and an elevated integrated relaxation pressure. With RDC pan-esophageal pressurization was observed and IRP is increased further (mean IRP 31 mm Hg vs. IRP-RDC 37 mm Hg). This effect is observed only in achalasia and functional EGJ/LES outlet obstruction [41]. (c) Increased sensitivity of HRM study with adjunctive RDC. SWS is associated with aperistalsis and IRP within normal levels (12 mm Hg) for single water swallows (SWS). The criteria for pan-esophageal pressurization (>20 mm Hg) were not fulfilled. With RDC functional obstruction at the EGJ is obvious. IRP increased to 45 mm Hg and pan-esophageal pressurization was obvious. These findings identify impaired EGJ relaxation in achalasia type I with low baseline LES pressure. (d) Increased sensitivity of HRM study with adjunctive test meal. HRM during SWS (top panel) and during solid test meal (lower panel) in patient with persistent dysphagia after fundoplication surgery. SWS is associated with normal peristalsis; however, with solids, there is compartmentalized pressurization above the EGJ indicative of obstruction due to a slipped or twisted fundoplication wrap (confirmed at redo surgery)


Endoluminal Functional Lumen Imaging Probe (Endo-FLIP)


The endoluminal functional lumen imaging probe (Endo-FLIP) is a recently described technique that uses impedance planimetry to determine multiple cross-sectional areas (CSA) within a cylindrical bag during volume-controlled distension [44]. This approach provides a measure of esophagogastric junction (EGJ) distensibility (CSA/intrabag pressure). EGJ distensibility has been evaluated in patients before and after treatment for achalasia. The results correlated well with esophageal emptying on timed barium esophagogram and clinical response based on Eckardt score < 3 [4446]. More recently, FLIP topography demonstrated esophageal contractility in Type I and Type II achalasic patients who did not show any contractions on manometry. In addition, a unique feature of repetitive retrograde contractions was observed in Type III achalasic patients [47]. These findings suggest a potential novel method of Endo-FLIP technique to evaluate EGJ distensibility and eosphageal contractility. This could increase diagnostic sensitivity to motility disorders; however, its clinical utility is not proven.


Treatment


The aim of all therapeutic options for achalasia and EGJOO is to reduce the resistance to bolus passage across the EGJ. The available methods include pharmacotherapy, botulinum toxin injections, endoscopic dilatation, and myotomy which can be performed either surgically or by endoscopy (per-oral endoscopic myotomy [POEM]) [48]. The following section considers each of these options and then reviews studies that assessed the relative efficacy of pharmacologic, endoscopic, and surgical treatment.


Pharmacology Including Botulinum Toxin


In achalasia and functional causes of EGJOO calcium channel blockers and nitrates relax gastrointestinal smooth muscle and reduce LES pressure. Data from randomized controlled studies is lacking; however, this effect appears to improve dysphagia in some cases [49]. Sublingual nifedipine (10–30 mg, 30–45 min before meals) or isosorbide dinitrate (ISDN 5–10 mg, 15 min before meals) can be useful as short-term measures in patients who are poor candidates for myotomy or endoscopic dilatation. However, these drugs are often associated with side effects including headache, orthostatic hypotension, and edema and do not retard disease progression. The 5′-phosphodiesterase inhibitors, such as sildenafil (Viagra®), reduce LES pressure and can attenuate distal esophageal contractions. This medication works by blocking the enzyme that degrades nitric oxide and increasing local concentration of this inhibitory neurotransmitter in the smooth muscle [50]. The lack of long-term data and cost issues have largely restricted the off-label use of sildenafil in achalasia.

Injection of botulinum toxin into the lower esophageal sphincter blocks the release of acetylcholine from nerve endings and reduces LES pressure in achalasia [51]. In one study up to 66% of achalasia patients achieved improvement in dysphagia after 6 months [52]. However, the therapeutic effect wears off due to axonal regeneration, with a meta-analysis reporting symptomatic response rates after one injection of 78%, 70%, 53%, and 41% at 1 months, 3 months, 6 months, and 12 months, respectively [53]. Repeated treatments with Botox have been associated with inferior response rates compared to subsequent Heller myotomy [54]. Based on the above findings, botulinum toxin injection is generally applied only in elderly patients with multiple comorbidities that are unfit for more definitive treatments [29].


Endoscopic Dilation


Endoscopic dilation aims to improve bolus transport by mechanically disrupting the EGJ/LES. In cases of structural EGJOO due to tight peptic or inflammatory strictures Savary bougie dilatation of the EGJ is most appropriate since the risk of esophageal perforation by a large balloon is high. In achalasia, functional EGJOO and other causes of structural EGJOO (e.g., post-fundoplication) pneumatic dilatation are performed. A noncompliant balloon (e.g., Rigiflex, Boston Scientific, USA) is positioned across the EGJ over an endoscopically inserted guidewire. The position of the balloon is confirmed fluoroscopically and controlled dilation is performed according to the manufacturer’s instructions until the balloon is fully expanded [55]. A graded approach is recommended with increasing balloon diameters (3.0, 3.5, and 4.0 cm) spaced 2–4 weeks apart depending on symptom relief [21, 56], residual LES pressures [21, 57] or improvement in timed barium esophageal (TBE) emptying [5860].

Pneumatic dilatation is safe and effective in the majority of patients; however, response rates are lower in patients that are young (<40 years) and male gender [61], and those with elevated LES pressure and in Type I achalasia (with gross dilatation) and Type III achalasia (with spasm) [13, 22, 62]. Further, a gradual loss of remission occurs with time in many patients [21, 63, 64]. A study from the Cleveland clinic [55] reported a 62% success rate at 6 months and 28% success rate at 6 years in patients who had undergone a single pneumatic dilatation , whereas serial dilation improved symptom response to 90% at 6 months and 44% at 6 years. Overall, approximately one-third of patients experience symptom relapse after 4–6-year follow-up but are often responsive to repeat pneumatic dilatation [21].

The most important complication of pneumatic dilation is esophageal perforation. A systematic review reported a risk of 1% which was comparable to the risk of unrecognized perforation during Heller myotomy [65]. In general, these perforations can be managed conservatively, although there is an associated mortality [63]. Risk factors for perforation include a large balloon diameter, old age, and Type III achalasia [21, 57, 66].


Surgical Heller Myotomy


Surgical treatment of achalasia by Heller myotomy was first reported by Ernst Heller in 1914 and is considered the most definitive treatment. In current practice laparoscopic Heller myotomy (LHM) is preferred because it provides an enhanced view of the muscle layer and allows a meticulous dissection of the transverse fiber bundles. The laparoscopic approach has a lower morbidity and comparable long-term outcome compared to the thoracoscopic or transabdominal approach [67]. The reported perforation rate occurring from LHM is 3.1% with the majority occurring during surgery and repaired immediately [68]. An antireflux procedure [69] performed in the same operation decreases the risk of postoperative gastroesophageal reflux after LES disruption [70]. A recent large-scale study [71] reported a prevalence of GERD of 8.6% at 6 months using 24-h esophageal pH evaluation in patients who had undergone prior LHM with a Dor fundoplication.

The LHM procedure has efficacy rates between 88 and 95% [62, 72, 73]. Predictors of a good outcome include younger age (<40 years) and a high resting LES pressure (>30 mm Hg) [7476]. A large sigmoid shaped esophagus as seen in achalasia type I carries a worse prognosis [7476]; however, surgery is still the preferred modality in this situation since the efficacy of pneumatic dilatation is very poor in this situation.


Per-Oral Endoscopic Myotomy (POEM)


POEM is an endoscopic technique that applies the principles of natural orifice transluminal endoscopic surgery (NOTES) to perform LES myotomy in achalasia. The technique was initially described by Pasricha [77] and further developed by Inoue [78]. It involves creating a submucosal tunnel from the mid-esophagus and dissecting the mucosa downwards to reach the cardia. This is followed by selective myotomy of the circular muscle fibers for a minimum length of 6 cm up the esophagus and 2 cm distal to the squamocolumnar junction onto the gastric cardia. Success rates of POEM [7982] are high in the short term but efficacy decreases with time from 97% at 3 months to 82% at 1 year [83]. The major side effect of POEM is the development of gastroesophageal reflux disease (GERD). A systematic review of five studies that have used esophageal pH monitoring to evaluate patients after POEM reported a 43% prevalence of pathological acid exposure [84]. This was confirmed in a recent series of 103 patients with a prevalence of 51% abnormal pH studies with esophagitis in 29% [85]. Although POEM is now performed in many centers, there is a lack of long-term outcome data comparing its efficacy with conventional techniques of endoscopic dilatation and surgical myotomy.

Appropriate patient selection for POEM has not been established. Advocates of the technique have treated patients with all forms of achalasia, prior treatment with Botox [86], prior treatment with pneumatic dilation [86, 87], and who have failed surgical myotomy [8890]. In a recent multicentre retrospective analysis of the 2-year outcome after POEM, the overall success rate was 80% [91]. Analysis by achalasia subgroups showed similar efficacy in Type I achalasia (75%), Type II achalasia (79.2%), and Type III achalasia (75%) [91]. Most experts do not use POEM in patients with gross dilatation or other, anatomical abnormalities of the distal esophagus (e.g., diverticulum). However successful POEM in patients with sigmoid achalasia has been reported [92].

The most common complication of POEM is GERD. Reflux symptoms and reflux esophagitis occur frequently and are a logical consequence of LES disruption without an antireflux procedure [82]. The frequency of endoscopic features of reflux esophagitis (Grade A/B) was 38% at 2-year follow-up [91]. One case has been reported of severe reflux esophagitis with resultant peptic stricture that required endoscopic dilatation [82]. It seems likely that the risk of postprocedural reflux is higher in patients with central adiposity and this could explain the increased risk of GERD in American and European case series compared to original reports from Japan. Proton pump inhibitors (PPIs) should be used routinely in all patients with symptoms and are prescribed routinely by many experts [82].


Esophagectomy for End-Stage Achalasia


Between 2 and 5% of patients will develop end-stage achalasia, defined as a massive dilation of the esophagus (diameter > 6 cm) with retention of food, persistent reflux disease, or presence of preneoplastic lesions [93]. Pneumatic dilation is less effective in this situation but studies have shown symptomatic improvement in 72–92% [94, 95] of patients with a megaesophagus who undergo Heller myotomy. Nevertheless esophagectomy is an option in patients with severe symptoms and objective evidence of very poor clearance after other treatments. It is also appropriate in patients with severe squamous dysplasia or Barrett esophagus with high-grade dysplasia to reduce the risk of invasive carcinoma [96].


Comparison of Treatment Modalities



Botulinum Toxin vs. Pneumatic Dilatation and Laparoscopic Heller Myotomy


A meta-analysis of controlled studies comparing outcomes at 1 year showed superior response rates from pneumatic dilation compared to botulinum toxin (66% vs. 36% [RR 2.0 (95% CI 1.51–3.20), p < 0.0001]) [97]. Similarly, a Cochrane review [98] that compared the outcome of patients who had undergone PD versus Botox showed no significant difference in remission at 4 weeks, but at 6-month follow-up, 46/57 PD patients achieved remission compared to 29/56 in the Botox. This benefit was maintained at 12 months in the PD group (55/75 in remission) compared to the Botox group (27/72 in remission) giving a risk ratio of 1.88 (95% CI 1.35–2.61, p = 0.0002) [98]. Table 1.4 summarizes studies [99106] which compared botulinum toxin injection to pneumatic dilation. Comparison of response rates of Heller myotomy compared to botulinum toxin therapy at 1 year also showed superior response rates for surgery (83% vs. 65% [RR 1.28, CI 1.02–1.59, p < 0.0001]) [97].


Table 1.4
Comparison of treatment outcome with pneumatic dilation compared to intrasphincteric application of botulinum toxin A at endoscopy

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Jan 31, 2018 | Posted by in ABDOMINAL MEDICINE | Comments Off on Achalasia and Esophageal Outlet Obstruction
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