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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  Achalasia, an oesophageal motor disease, is associated with functional oesophageal obstruction. Food stasis can predispose for oesophagitis. Treatment aims at lowering of the lower oesophageal sphincter pressure, enhancing the risk of gastro-oesophageal reflux. Nevertheless, the incidence of oesophagitis after achalasia treatment is unknown.

Aim  To investigate the incidence and severity of oesophagitis in achalasia patients treated with pneumatic dilatation.

Methods  A cohort of 331 patients with achalasia were treated with pneumatic dilatation and followed. Oesophagitis and stasis were assessed by endoscopy and inflammation was graded by histology.

Results  251 patients were followed for a mean values of 8.4 years (range: 1–26). The average number of endoscopies with biopsy sample sets per patient was 4 (range: 1–17). Three patients had no histological signs of oesophagitis throughout follow-up, 139 had oesophagitis grade 1, 49 oesophagitis grade 2 and 60 grade 3. Specialized intestinal metaplasia was found in 37 patients. The association between endoscopic food stasis and histological inflammation was significant. The association between endoscopic signs of oesophagitis and histological inflammation was poor.

Conclusions  Forty percent of the achalasia patients develop chronic active or ulcerating oesophagitis after treatment. Inflammation was associated with food stasis. Because the sensitivity of endoscopy to detect inflammation is low, surveillance endoscopy with biopsy sampling and assessment of stasis is warranted to detect early neoplastic changes.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Achalasia is an uncommon disorder with a largely unknown aetiology, in which there is a loss of relaxation of the lower oesophageal sphincter (LES) and a peristalsis of the distal part of the oesophagus.1 Treatment options are merely symptomatic and aim at lowering the LES pressure to improve the passage of fluid and food. Pneumatic dilatation and laparoscopic myotomy are the two most commonly applied treatment modalities. Pneumatic dilatation is an effective treatment with low complication risk and can be performed as an out-patient procedure.2–4

Lowering LES pressure not only intends to improve food passage but may also increase gastro-oesophageal reflux. Such reflux is thought to be quite common after surgical myotomy, for this reason myotomy is often combined with an antireflux procedure.5 A previous study has reported that symptomatic reflux also may occur in patients after pneumatic dilatation.6 Complications of gastro-oesophageal reflux, such as Barrett's metaplasia and adenocarcinoma of the oesophagus in patients treated for achalasia are incidentally reported.7–9

Patients with achalasia also have an increased risk of developing squamous cell carcinoma of the oesophagus. This is probably due to chronic inflammation and hyperplasia of the epithelium in response to stasis of food and fluid.10 In oesophageal resection specimens from patients with achalasia and oesophageal squamous cell carcinoma, a marked hyperplasia was found together with multiple dysplastic foci, which findings supports this hypothesis.11

Even though achalasia patients thus have various significant risk factors for the development of chronic oesophagitis, a condition with long-term implications, little is known about the prevalence of this disorder in achalasia patients during follow-up. We therefore studied the incidence and severity of oesophagitis in patients treated with pneumatic dilatation.

Material and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patients

Between 1975 and 2003 all patients with achalasia referred to the Erasmus MC Rotterdam were diagnosed, treated and followed according to a strict protocol which did not change over time and which was carried out by a limited number of doctors. Achalasia was diagnosed by oesophageal manometry. A peristalsis of the distal part of the oesophagus and loss of relaxation of the LES were considered diagnostic for achalasia. This diagnosis was supported by a timed barium esophagram in which stasis of contrast, a bird beak appearance and widening and elongation of the oesophagus were considered compatible with achalasia. An upper gastrointestinal (GI) endoscopy was performed to rule out secondary achalasia resulting from a neoplastic lesion. The treatment protocol consisted of three dilatation sessions on three consecutive days using Rigiflex balloon dilator (Boston Microvasive, Boston, MA, USA) with an increasing diameter of 30, 35 and 40 mm. The balloon was positioned in the LES under fluoroscopic control and easily insufflated to a pressure of 300 mmHg and kept insufflated for 1 min. During insufflation there was attention for a waist and its possible disappearance. Treatment success was defined as relieve of symptoms (in particular regurgitation, vomiting and weight loss) regardless of improvement of the esophagram. Disease recurrence, was defined as deterioration of symptoms, and was primarily treated with pneumatic dilatation, whereas a myotomy was performed in patients who had responded poorly to previous dilatation. Patients were seen after 1, 2, 4 and 7 years of follow-up. This included recording of the medical history, use of medication and body weight. In addition oesophageal manometry, upper GI endoscopy and a timed barium esophagram was performed. Seven years after initial treatment, follow-up was continued 3-yearly by upper GI endoscopy with biopsy sampling.

Upper GI endoscopy and biopsy sampling

At each upper GI endoscopy, the oesophagus and gastro-oesophageal junction were inspected for the presence of macroscopic oesophagitis and, in a proportion of the endoscopies posterior, graded according the Los Angeles classification (grades A–D),12 Barrett's metaplasia, carcinoma and stasis of food (mild in case of retention of fluid only, moderate in case of some fluid and solids and severe when there is massive retention in which it was impossible to inspect the mucosa). Three to four biopsy specimens were sampled with standard forceps just above the gastro-oesophageal junction. If there was suspicion of columnar metaplasia, dysplasia or carcinoma, additional biopsies were obtained. In case of severe stasis, extensive irrigation and suction were applied to clean the oesophagus. When this remained unsuccessful and proper examination of the mucosa remained impossible, the endoscopy was repeated after 3 days of liquid diet.

Histology

About 4 μm haematoxylin–eosin-stained routine histological sections were used. An experienced GI pathologist blinded to the clinical data re-evaluated all samples. Oesophagitis was assessed according to established criteria.13–15 Using these criteria, the following lesions were considered compatible with reflux disease of increasing severity: (i) basal layer hyperplasia, (ii) elongation of papillae, (iii) dilation of papillary vascular spaces, (iv) intraepithelial inflammatory infiltration, (v) mucosal erosion and (vi) granulation tissue. For practical purposes inflammation was graded into chronic (i.e. oesophagitis grade 1, in the presence of criteria 1–3), chronic active (i.e. oesophagitis grade 2, in the presence of criteria 4 with or without criteria 1–3), or eroding ulcerating (i.e. oesophagitis grade 3, in the presence of criteria 5 or 6; Figure 1). In addition to this inflammatory score, the presence of intestinal metaplasia, dysplasia or neoplasia was recorded.

image

Figure 1. Oesophageal biopsy samples, haematoxylin–eosin (H and E)-stained; all magnifications 20× objective except (4: 10× objective). (1) Epithelial hyperplasia, elongation of papillae and dilated vascular spaces (oesophagitis grade 1). (2) Intraepithelial inflammatory infiltrate with an occasional eosinophil (oesophagitis grade 2). (3) Granulation tissue (oesophagitis grade 3). (4) Erosion and ulcers (oesophagitis grade 3).

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Statistics

In order to assess the association between histological inflammation and stasis, we applied a logistic regression model with random effect to correct for the fact that in each patient a different number of biopsy samples were taken. We assumed an autoregressive correlation structure between measurements within a patient applying proc genmod with the repeated statement in sas 8.2. Correction for age, which had a significant effect, was made. The effect of smoking behaviour was not significant and therefore no correction was made in a group with a surprisingly low number of smoking patients. To assess the association between microscopic and macroscopic inflammation we used this logistic regression model in a similar way. P-values of <0.05 were considered significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Between 1975 and 2003, 331 patients (160 male, mean age 50.3 years, range: 4–92) with achalasia were treated with pneumatic dilatation. Seventy-two patients (22%) were excluded from this analysis for reasons of missing data (n = 37), or because biopsy sampling was not performed (n = 35). In total, 259 patients were included in the final analysis. A total of 1238 biopsy sample sets (containing 4333 biopsy specimens) had been obtained from these patients, 111 sample sets were excluded from the analysis because the slides could not be found in the archive (n = 25), the slides were technically not evaluable (n = 3), in the slides no squamous epithelium or intestinal metaplasia or carcinoma was present (n = 59), or a missing endoscopic report (n = 24). In 25 sample sets, no squamous epithelium was present and therefore inflammation could not be assessed but there were signs of intestinal metaplasia or carcinoma. In total, in 1102 samples from 251 patients sufficient squamous epithelium allowed histological assessment of inflammation and the corresponding endoscopic report was available. The mean follow-up of these patients was 8.4 years (range: 1–26). A mean of four sample sets per patient had been obtained over time (range: 1–17).

One hundred and sixty-five (65.7%) patients had no endoscopic signs of oesophagitis throughout the observation period. 55 (21.9%) showed endoscopical oesophagitis grade A, 17 (6.8%) grade B, nine (3.6%) grade C and five (2%) showed grade D. Twenty-five (10%) patients developed endoscopical signs of a segment of columnar epithelium in the distal oesophagus suggesting Barrett's metaplasia. In 13 (5%) patients, a solitary ulcer was seen at least at one occasion during follow-up.

Histological signs of oesophagitis were scored according to the highest level of inflammation per patient during follow-up. Chronic active or ulcerating oesophagitis [grade 2 (n = 49) or 3 (n = 60)] was found in 109 of 251 (43.4%) patients during follow-up. Chronic oesophagitis (grade 1) was seen in 139 (55.4%) patients and only three (1.2%) patients had no inflammation (grade 0) during follow-up. After a mean of 12 years of follow-up (range: 7–17) 50% of the patients developed moderate to severe inflammation (being grade 2 or 3) in the biopsy samples (Figure 2).

image

Figure 2. Probability of survival without moderate to severe oesophagitis as assessed by histology in years after the first dilatation series (1) and after first (2) and second (3) retreatment because of symptom recurrence.

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Low-grade dysplasia (LGD) in squamous cell epithelium developed in 11 of 251 (4.4%) patients after a mean follow-up of 6 years (range: 0–12) after pneumatic dilatation and 14.5 years (range: 9–29) after the start of symptoms. One of these patients developed squamous cell carcinoma 33 years after the start of symptoms, whereas one patient developed carcinoma in situ 29 years after the start of symptoms. Squamous cell carcinoma developed in seven of 251 (2.8%) patients after a mean follow-up of 20.4 years (range: 2–33) after the start of symptoms and 10 years (range: 1–23) after the initial treatment.

Barrett's metaplasia (defined as the presence of intestinal metaplasia) was histological detected in 37 of 251 (14.7%) patients after a mean follow-up of 6.0 years (range: 0–28) after initial treatment. From these 37 patients, 12 (32.4%) developed LGD, one high-grade dysplasia (HGD) and three patients with adenocarcinoma.

The estimated predicted value for the presence of histological inflammation in the presence of endoscopic oesophagitis was only significant for grades B–D (P = 0.0013). In 28 of 53 (52.8%) of the samples, taken from an oesophagus with endoscopic oesophagitis grade B, C or D, histological inflammation grade 2 or 3 was found. However, 156 of 895 (17.4%) of the biopsy samples obtained from patients without endoscopic oesophagitis also showed grade 2 or 3 inflammation (Table 1, Figure 3).

Table 1.  Prediction of histological inflammation with upper and lower confidence limit in the absence of endoscopical signs of oesophagitis (0) and in the presence of oesophagitis grade A (1) and oesophagitis grades B, C and D (2)
OesophagitisInflammationP-value
Odds ratio95% confidence interval
None1.0  
Grade A1.40.86–2.40.17
Grade B, C, D3.91.7–9.00.0013
image

Figure 3. Prediction of moderate to severe (grades 2 and 3) histological inflammation (%) with upper and lower confidence limit in the absence of endoscopical signs of oesophagitis (0) and in the presence of oesophagitis grade A (1) and oesophagitis grades B, C and D (2).

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Assuming the histological investigation as the gold standard for the assessment of inflammation, the sensibility and specificity of endoscopy for oesophagitis was 37.6% (range: 31–44) and 83.6% (range: 81–86) respectively.

The odds ratios showed a significant association between food stasis and the grade of histological inflammation, which was also present after correction for age and number of samples per patient. With increasing severity of food stasis during endoscopy, the odds ratio increased up to 4.5 in case of severe stasis (P < 0.0001; Table 2, Figure 4).

Table 2.  Prediction of histological inflammation with upper and lower confidence limits when there is no stasis (0), mild stasis (1), moderate stasis (2) and severe stasis (3)
StasisInflammation P-value
Odds ratioConfidence limits
01.0  
11.61.0–2.50.049
22.61.5–4.60.0012
34.52.6–7.9<0.0001
image

Figure 4. Prediction of moderate to severe (grades 2 and 3) histological inflammation (%) with upper and lower confidence limits in patients who either have no food stasis (0), mild stasis (1), moderate stasis (2) and severe stasis (3).

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In this study, which started in 1975, different acid-suppressive therapies were used, usually for short periods after diagnosing oesophagitis at endoscopy. In almost all cases, these therapies had been withdrawn long before the next surveillance endoscopy was performed and individual patients used different kinds of acid-suppressive therapies during follow-up. We analysed the data of medication use, which was recorded in the medical chart. If there was no information regarding medication, we assumed no acid-lowering medication was taken. We made a distinction between proton-pump inhibitors (PPI), H2-antagonist and other (mostly topical) medication.

Sixty-eight (27%) patients used acid-suppressive therapy at any time during a follow-up endoscopy, thus 243 (22%) of the 1102 endoscopies were performed while the patient was using acid-suppressive therapy (89 endoscopies in 32 patients during PPI treatment, 81 endoscopies in 30 patients during H2-antagonists and 73 endoscopies in 35 patients during other treatment). Patients taking acid-lowering therapy other than PPIs or H2-antagonists showed significantly more inflammation grades 2 and 3 than the untreated group (34% vs. 18%, P = 0.001). The difference in prevalence of inflammation grades 2 and 3 between the patients on PPIs or H2-antagonists vs. the untreated patients was not significant (17% and 26% vs. 18%; P = 0.720, respectively 0.110).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

The treatment of achalasia aims at reduction of the LES pressures to relieve dysphagia. This is usually achieved by pneumatic dilatation or myotomy, techniques which may induce significant sphincter insufficiency. Gastro-oesophageal reflux, which may result from this insufficiency, is able to cause oesophagitis. On the other hand, insufficient treatment of the non-relaxing sphincter may lead to stasis of food, which can also predispose to oesophagitis. This intricate balance suggests that oesophagitis is likely to be a common condition in achalasia patients, yet there has to our knowledge no data regarding this issue been published.

Our results show that chronic active oesophagitis is indeed very common in achalasia patients after dilatation therapy. In our series, nearly all patients showed histological evidence of chronic oesophagitis. Most of them showed active inflammation with erosive histological lesions, and these lesions largely remained unchanged over time. The prevalence of inflammation was lower when judged by endoscopy; however, also endoscopy showed macroscopic evidence of oesophageal inflammation in a considerable proportion of patients. Thirty-six percentage of patients showed macroscopic signs of oesophagitis, being grade B to D in 12% of them. The sensitivity of endoscopy to detect inflammation of the oesophageal mucosa is low, which among others, can be explained by limitations of endoscopical inspection in patients with often mucosal adherence of food, even after fasting. We applied the Los Angeles classification because of its widespread application and usefulness in clinical practice, even though this classification was not primarily developed for patients with food stasis and achalasia.

It is difficult to differentiate between inflammation caused by acid reflux or food stasis. It is well known that achalasia patients even at first presentation prior to therapy can complain of heartburn.16, 17 The aetiology of which is still unclear. The histological picture did not allow a clear differentiation and therefore we differentiated by endoscopy on the basis of the presence of food stasis on one hand vs. oesophagitis without evidence of food stasis on the other.

Stasis of food is common in achalasia patients, also after dilatation treatment. This condition is often neglected as irrelevant when not accompanied by deterioration of symptoms. We however, observed a significant association between stasis of food and the histological presence of inflammation. Chronic stasis is thought to contribute to mucosal hyperplasia, which can be complicated by multifocal dysplasia. This may after many years gives rise to an increased risk of developing a squamous cell carcinoma.11 Together, this warrants a more active approach towards achalasia patients with persisting moderate or marked stasis of oesophageal contents. In order to reduce chronic inflammation and its complications, patients with chronic stasis or eroding ulcerative oesophagitis may require repeated dilatation treatment or myotomy, probably even independent of their reported symptoms. The association between symptoms, oesophagitis and stasis is only moderate. Patients with achalasia tend to underreport their symptoms, because they are used to an often long-standing situation of dysphagia and interpret a slight improvement in oesophageal emptying as already a dramatic improvement.3, 18 Besides, many achalasia patients, especially those who are older have an altered vagal afferent response leading to a diminished perception of pain.19, 20

In order to detect inflammation, surveillance endoscopy with adequate biopsy sampling is necessary. The interval between the surveillance endoscopies needs further investigation and this may be dependent on the level of inflammation. The importance of grade 1 inflammation (basal layer hyperplasia, elongation of papillae and dilation of papillary vascular spaces) that occurred in nearly all our patients, is likely to be limited. But when more severe inflammation such as histological grade 3 (granulation, ulcers) remains present despite adequate therapy, more intensive surveillance should be offered, probably every year starting 10 years after the onset of symptoms, when it is known that the risk of developing a carcinoma is increasing.21, 22 As surveillance endoscopies can be technically very difficult in achalasia patients, we should prescribe a 3-day liquid diet before the endoscopy to allow better inspection of the oesophageal mucosa. During endoscopy, the use of lugol staining may help to identify high-risk lesions and allow directed biopsy sampling.23 When LGD is detected during endoscopy, surveillance intervals should be intensified and in case of HGD we suggest oesophagectomy because of the frequent multifocal character of the dysplasia.7

Our study did not provide an answer to the question whether a symptomatic relapse of achalasia affects oesophagitis. This limitation was due to the fact that in a great proportion of our patients no samples were taken at the time of symptom relapse and mostly these relapses occurred between surveillance intervals.

There was no significant difference in inflammation between patient using PPIs or H2-antagonists and the patients without acid-lowering therapies. However, we analysed the data of medication use as recorded in the medical chart. If there was no information regarding medication, we assumed no acid-lowering medication was taken, which may be a wrong conclusion. Besides different kinds of acid-lowering therapies were used for usually small periods in our patient groups and individual patients used different kinds of acid-suppressive therapies during follow-up.

In conclusion, our study shows that oesophagitis is a very common condition in patients with achalasia. Almost all patients with achalasia treated with pneumatic dilatation develop chronic oesophagitis during follow-up. The sensitivity of endoscopy for assessment of oesophagitis in these patients is poor, but there is a significant association between endoscopic signs of food stasis and the presence of oesophagitis. The latter may lead to hyperplasia, dysplasia and development of squamous cell carcinoma. For this reason, the presences of food stasis or histological oesophagitis grade 3 forms in our opinion an indication for retreatment by pneumatic dilatation or myotomy even in the absence of deterioration of symptoms.

This warrants a more active approach in the follow-up of patients with achalasia and requests for surveillance endoscopy with biopsy sampling in patients with achalasia after treatment with pneumatic dilatation to evaluate stasis and inflammation in biopsy samples.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
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