Esophageal achalasia with mucosal damage due to enteric-coated aspirin.

A 76-year-old man was referred to our hospital for examination and treatment of dysphagia. He has been taking enteric-coated aspirin for myocardial infarction. Esophagogastroduodenoscopy (EGD) revealed the presence of esophageal ulcers in the distal esophagus and five to six tablets of enteric-coated aspirin. The esophageal ulcers were believed to have been caused by the retention of aspirin within the esophagus due to achalasia. We substituted enteric-coated aspirin with powdered aspirin. A follow-up EGD performed 1 month later showed improvement of esophageal mucosa. The patient was diagnosed with type I achalasia. Per-oral endoscopic myotomy was performed, and his symptoms improved after the procedure. Although a few studies have investigated the direct effect of aspirin, none of them has reported on the direct effect of aspirin on the esophagus. It might be effective to administer powdered aspirin for patients with achalasia to prevent esophageal ulcers caused by the direct effect of aspirin.

Endoscopic ultrasound: a powerful tool to modify treatment algorithms in opioid-induced achalasia.

BACKGROUND: Opioid use in the U.S. has increased dramatically over the last 15 years, recently being declared a public health emergency. Opioid use is associated with esophageal dysmotility lending to a confusing clinical picture compared to true achalasia. Patients exhibit symptoms and elicit diagnostic results consistent with esophageal motility disorders, in particular type III achalasia. Modified therapeutic strategies and outcomes become challenging. Differentiating true achalasia from opioid-induced achalasia is critical. Conventional surgical interventions, i.e., myotomy, are ineffective in the absence of true achalasia. We assess the utility of esophageal muscle layer mapping with endoscopic ultrasound (EUS) in distinguishing primary from opioid-induced achalasia. METHODS: From 2016 to 2019, patients with abnormal manometry and suspected achalasia underwent esophagogastroduodenoscopy and EUS mapping of esophageal round muscle layer thickness. Maximum round layer thickness and length of round muscle layer thickness > 1.8 mm were collected and compared between opioid users and non-opioid users using Wilcoxon Rank sum test. RESULTS: 45 patients were included: 12 opioid users, 33 non-opioid users. Mean age 56.8 years (range 24-93), 53.3% male patients. Mean BMI in the opioid-induced achalasia group was 30.2 kg/m2, mean BMI in the primary achalasia group 26.8 kg/m2 (p = 0.11). In comparing endoscopic maximum round layer thickness between groups, non-opioid patients had a thicker round muscle layer (2.7 mm vs 1.8 mm, p = 0.05). Length of abnormally thickened esophageal muscle (greater than 1.8 mm) also differed between the two groups; patients on opioids had a shorter length of thickening (4.0 cm vs 0.0 cm, p = 0.04). Intervention rate was higher in the non-opioid group (p = 0.79). Of the patients that underwent therapeutic intervention, symptom resolution was higher in the non-opioid group (p = 0.002), while re-intervention post-procedure for persistent symptomatology was elevated in the opioid subset (p = 0.06). Patients in the opioid group were less likely to undergo invasive treatment (Heller). As of 2017 all interventions in the opioid group have been endoscopic. CONCLUSION: Endoscopic ultrasound is an essential tool that has improved our treatment algorithm for suspected achalasia in patients with chronic opioid usage. Incorporation of EUS findings into treatment approach may prevent unnecessary surgery in opioid users.

Anticholinergic, anti-depressant and other medication use is associated with clinically relevant oesophageal manometric abnormalities.

BACKGROUND: Medications can affect gastrointestinal tract motility. However, their effects on oesophageal motility in particular are often not as widely known or may be underestimated. AIM: To review the effect of existing medication use on high-resolution oesophageal manometry (HRM) in a 'real-world' setting. METHODS: Adult patients with upper gut symptoms and normal endoscopy or imaging who had HRM over a 22-month period were analysed. Achalasia and major disorders of peristalsis were excluded. All medications taken within 24 hours of the procedure were prospectively recorded and compared with HRM results, controlling for age, gender and proton pump inhibitor use. RESULTS: A total of 502 patients (323 female, mean age 51) were recruited. Of these, 41.2% had normal oesophageal HRM, while 41.4% had ineffective oesophageal motility (IOM) and 7.6% had oesophagogastric junction outflow obstruction (OGJOO). Serotonin/norepinephrine reuptake inhibitors (SNRI) and opioids were associated with significantly higher resting lower oesophageal sphincter pressure. Benzodiazepines and opioids were associated with elevated integrated relaxation pressure. SNRI and inhaled beta-agonists were associated with increased distal contractile index, whereas calcium channel blockers were associated with a lower distal contractile index. Odds ratio of being on anticholinergics was higher in IOM patients vs normal (3.6, CI 1.2-10.8). Odds ratio for anticholinergics, inhaled beta-agonists, anticonvulsants, SNRIs and opioids (trend) were all > 3 for OGJOO patients vs normal. CONCLUSION: Many medication classes are associated with abnormal HRM variables and diagnoses such as OGJOO and IOM; some of these associations are probably causal. These possible links should be taken into consideration during manometry interpretation.

Aflatoxin influences achalasia symptomatology.

Achalasia is characterized by impaired swallowing due to lower esophageal sphincter (LES) dysfunction and an increased risk of esophageal carcinoma. Aflatoxin is a known carcinogen. Esophageal retention is relieved by per oral endoscopic myotomy (POEM), which lowers the esophageal cancer risk. The present study determined whether aflatoxin is involved in the pathogenesis of achalasia or esophageal cancer. A total of 75 patients with achalasia were prospectively enrolled from a tertiary center. Aflatoxin levels in their esophageal contents were measured using ELISA, and esophageal mucosal specimens were immunohistochemically evaluated for Ki67 and p53 expression prior to and 3 months after POEM. The effect of aflatoxin on esophageal contractility was assessed using murine specimens. Aflatoxin was detected in 67 patients before POEM and only 2 patients after POEM. The number of Ki67­ and p53­immunopositive cells in the esophageal mucosa significantly decreased after POEM: [Ki67: 27.8% (95% confidence interval (CI), 25.98­29.70) vs. 20.7% (95% CI, 19.78­24.03), P=0.04 and p53: 2.14% (95% CI, 1.85­2.41) vs. 1.45% (95% CI, 1.22­1.68), P=0.03]. In vitro experiments revealed that 500 ng/ml aflatoxin significantly increased the amplitude (P<0.05) and frequency (P<0.05) of spontaneous LES contractions compared with the control group. These increases were blocked by co­treatment with atropine sulfate (P<0.05), but not with a nitric oxide synthase inhibitor (P>0.05). Aflatoxin was found in most patients with achalasia and was eliminated following POEM. Reduced Ki67 and p53 expression after POEM indicated a decreased risk of carcinogenesis. Aflatoxin accumulation increased LES contractility via cholinergic signaling. Therefore, aflatoxin may maintain achalasia symptoms and increase esophageal cancer risk.

Opioid-Induced Esophageal Dysfunction: Differential Effects of Type and Dose.

OBJECTIVE: Data regarding opioid effects on esophageal function are limited. We previously demonstrated an association between chronic opioid use and esophageal motor dysfunction characterized by esophagogastric junction outflow obstruction, distal esophageal spasm, achalasia type III, and possibly Jackhammer esophagus. Our aim was to characterize the influence of different opioids and doses on esophageal dysfunction. METHODS: Retrospective review of 225 patients prescribed oxycodone, hydrocodone, or tramadol for >3 months, who completed high-resolution manometry from 2012 to 2017. Demographic and manometric data were extracted from a prospectively maintained motility database. Frequency of opioid-induced esophageal dysfunction (OIED, defined as distal esophageal spasm, esophagogastric junction outflow obstruction, achalasia type III, or Jackhammer esophagus on high-resolution manometry, was compared among different opioids. The total 24-hour opioid doses for oxycodone, hydrocodone, and tramadol were converted to a morphine equivalent for dose effect analysis. RESULTS: OIED was present in 24% (55 of 225) of opioid users. OIED was significantly more prevalent with oxycodone or hydrocodone use compared with tramadol (31% vs 28% vs 12%, P = 0.0162), and for oxycodone alone vs oxycodone with acetaminophen (43% vs 21%, P = 0.0482). There was no difference in OIED for patients taking hydrocodone alone vs hydrocodone with acetaminophen. Patients with OIED were taking a higher median 24-hour opioid dose than those without OIED (45 vs 30 mg, P = 0.058). DISCUSSION: OIED is more prevalent in patients taking oxycodone or hydrocodone compared with tramadol. There is greater likelihood of OIED developing with higher doses. Reducing the opioid dose or changing to tramadol may reduce OIED in opioid users.

Lower prevalence of gastroesophageal reflux disease in patients with noncardiac chest pain on opiates: a cross-sectional study.

Opiates can cause heartburn and spastic esophageal dysmotility but their role in noncardiac chest pain (NCCP) is not known. Our aim was to characterize opiate effects on esophageal function using esophageal pH monitoring and high-resolution manometry (HREM) in these patients.We performed a cross sectional study of opiate users with NCCP who underwent HREM and esophageal pH study from 2010 to 2017 using opiate nonusers as a comparison group. Demographic data, symptoms, opiate use, endoscopic findings, esophageal pH study parameters, and HREM data were abstracted.Thirty three patients with NCCP on opiates were compared to 144 opiate non-users. Compared to opiate nonusers, opiate users had lower total acid exposure (2.3% vs. 3%, P = 0.012), lower upright acid exposure (1.2% vs. 3.1%, P = 0.032) and lower DeMeester score (6.5 vs. 12.7, P = 0.016). Opiate users also had higher lower esophageal sphincter integrated relaxation pressure (LES-IRP) (7.0 mm Hg [2.2, 11.7] vs. 3.7 mm Hg [1.1, 6.2] P = 0.011) and greater mean distal contractile integral (DCI) (2575 mm.Hg.s.cm [1134, 4466] vs. 1409 mm.Hg.s.cm [796, 3003] P = 0.03) than opiate non-users. The prevalence of hypertensive motility disorders (15.2% vs. 11.1%) and achalasia (12.1% vs. 2.1%) was higher in opiate users (P = 0.039) but did not reach significance on multivariate analysis.In patients presenting with NCCP, opiate users had lower esophageal acid exposure compared to opiate nonusers. This might be due to higher LES pressures preventing reflux and higher DCI leading to more rapid acid esophageal clearance.

Opioid-Induced Esophageal Dysfunction (OIED) in Patients on Chronic Opioids.

OBJECTIVES: Bowel dysfunction has been recognized as a predominant side effect of opioid use. Even though the effects of opioids on the stomach and small and large intestines have been well studied, there are limited data on opioid effects on esophageal function. The aim of this study was to compare esophageal pressure topography (EPT) of patients taking opioids at the time of the EPT (≤24 h) with chronic opioid users who were studied off opioid medications for at least 24 h using the Chicago classification v3.0. METHODS: A retrospective review identified 121 chronic opioid users who completed EPT between March 2010 and August 2012. Demographic and manometric data were compared between the two groups using general linear models or χ(2). RESULTS: Of the 121 chronic opioid users, 66 were studied on opioid medications (≤24 h) and 55 were studied off opioid medications for at least 24 h. Esophagogastric junction (EGJ) outflow obstruction was significantly more prevalent in patients using opioids within 24 h compared with those who did not (27% vs. 7%, P=0.004). Mean 4 s integrated relaxation pressure was also significantly higher in patients studied on opioids (10.71 vs. 6.6 mm Hg, P=0.025). Resting lower esophageal sphincter pressures tended to be higher on opioids (31.61 vs. 26.98 mm Hg, P=0.25). Distal latency was significantly lower in patients studied on opioids (6.15 vs. 6.74 s, P=0.044). CONCLUSIONS: Opioid use within 24 h of EPT is associated with more frequent EGJ outflow obstruction and spastic peristalsis compared with when opioid use is stopped for at least 24 h before the study.

Opiate-induced oesophageal dysmotility.

BACKGROUND: Opiates have well characterized (troublesome) untoward effects on the gastrointestinal tract. Opioid bowel dysfunction has been a subject of research and even drug design, but surprisingly little is known with regard to clinical effects of opiates on the oesophagus. AIM: To characterize opiate effects on motor function of the oesophagus in patients presenting with dysphagia. METHODS: Retrospective review of 15 patients with dysphagia referred for oesophageal manometry while on chronic opiates. Manometry was completed during opiate use and in three cases, after opiates were discontinued. RESULTS: All patients demonstrated motility abnormalities. Incomplete lower oesophageal sphincter (LOS) relaxation (11.5 +/- 1.6 mmHg) was seen in most cases. Ten patients demonstrated nonperistaltic contractions in > or =3 of 10 swallows. Additional abnormalities included high amplitude contractions; triple peaked contractions; and increased velocity. The average resting lower oesophageal sphincter (LOSP) met criteria for hypertensive LOS in three patients. These features were suggestive of spasm or achalasia. Repeat manometry off opiates was performed in three cases. LOS relaxation was noted to be complete upon repeat manometry in these cases. There was also improved peristalsis and normal velocity. CONCLUSIONS: A range of manometric abnormalities were seen in patients with dysphagia in the setting of opiate use: impaired LOS relaxation, high amplitude/velocity and simultaneous oesophageal waves. These data suggest that the oesophagus is susceptible to the effects of opiates and care must be taken before ascribing dysphagia to a primary oesophageal motility disorder in patients taking opiates.

A new experimental model to study preneoplastic lesions in achalasia of the esophagus

OBJETIVO: Desenvolver um modelo experimental que permitisse o estudo de lesões preneoplásicas induzidas por diethylnitrosamina em ratos com acalasia. MÉTODOS: Ratos Wistar machos foram distribuídos em quatro grupos: controle - C (n=8); ratos com megaesôfago - B (n=8); ratos tratados com DEN – D (n=15) e ratos com megaesôfago mais DEN - BD (n=15). O megaesôfago pode ser obtido experimentalmente através da aplicação tópica de cloreto de benzalcônio. Foi avaliada a morfologia do epitélio e a proliferação celular do epitélio pelo método do PCNA. RESULTADOS: A análise morfométrica mostrou aumento da espessura epitelial no grupo BD (2166±1012mm2) em relação aos outros grupos (C = 878±278mm2; B = 1746±144mm2 e D = 1691±697mm2), principalmente devido a uma hiperplasia da camada basal e um aumento na queratina da camada superficial. O índice de marcação pelo PCNA na camada basal foi significantemente maior neste mesmo grupo (0,695±0,111) quando comparado com os outros (C-0,490±0,132; B-0,512±0,215 e D-0,477±0,198). CONCLUSÕES: Estes dados confirmam através de um modelo experimental o aumento proliferativo celular durante o processo de carcinogênese na acalasia do esôfago e podem ser úteis durante estudos de endoscopia realizados em pacientes que possuem acalasia.

A new experimental model to study preneoplastic lesions in achalasia of the esophagus.

PURPOSE: Develop an experimental model to study esophageal preneoplastic lesions induced by diethylnitrosamine in rats with achalasia. METHODS: Male Wistar rats were divided into four groups: control--C (n=8); rats with megaesophagus--B (n=8); rats treated with DEN--D (n=15) and rats with megaesophagus plus DEN--BD (n=15). Megaesophagus can be experimentally obtained in rats by topical application of benzalkonium chloride. The morphology and PCNA labeling index of the epithelium were evaluated. RESULTS: The morphometric analysis showed an increase in epithelial thickness in the animals of group BD (2166+/-1012 mm2) when compared to the other groups (C = 878+/-278 mm2; B = 1746+/-144 mm2 and D = 1691+/-697 mm2), mainly due to basal layer hyperplasia, besides an increase in the keratin of the superficial layer. The PCNA labeling index in the basal layer was significantly higher in the group BD (0.695+/-0.111) when compared to the other groups (C = 0.490+/-0.132; B = 0.512+/-0.215 and D = 0.477+/-0.198). CONCLUSIONS: Our data confirm in an experimental model the previous observation in humans of increased epithelial cell proliferation during the esophageal carcinogenic process in achalasia and may be useful to further studies on the mechanisms of the esophageal carcinogenesis and the the design of follow-up endoscopic studies for patients with achalasia.

[Cardiotoxicity of 5-fluorouracil: report of 6 cases]. / Cardiotoxicité du 5-fluorouracil: à propos de 6 nouveaux cas.

5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the treatment of cancers of the digestive tract and breast. The clinical cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects include coronary disorders, heart failure and sudden death of suspected cardiac origin. Six new cases are reported, including 5 cases of angina and one of heart failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean: 56.2). They had no medical history of heart failure, myocardial ischemia or electrocardiographic anomalies prior to 5-FU treatment. Three patients had hypertension of whom one had had type-II diabetes mellitus for the past 20 years. Clinical symptoms included chest pain in 4 patients and heart failure in one, whereas the last patient had ECG changes with no associated clinical symptoms. Clinical symptoms of angina totally disappeared after the cessation of 5-FU administration, but heart failure was alleviated only after the introduction of digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients at greater risk are those with a history of ischemic cardiac disease, thoracic radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly elucidated. Spasms of the coronary arteries or toxic inflammation of the myocardium have been suspected. These 6 new cases confirm the potential for cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated patients.

Another case of achalasia-microcephaly syndrome.

The first German patient with achalasia-microcephaly syndrome is described. The mother was exposed to the anti-malarial drug Mefloquine during the first 8 weeks of pregnancy.

Megaesophagus in rats.

The objective of this study was to determine whether myenteric denervation of the abdominal esophagus using benzalkonium chloride (BAC) leads to esophageal achalasia with changes of the muscle propria and epithelial cell proliferation. The treatment led to megaesophagus 3 months after BAC application. Denervation of the esophagus induced muscle hypertrophy and increased epithelial cell proliferation. The imbalance of the neurotransmitters may play a role in these morphokinetic changes.

Electrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum.

BACKGROUND & AIMS: Achalasia is characterized by loss of myenteric neurons and incomplete relaxation of the lower esophageal sphincter (LES). The aim of this study was to develop an achalasia model in the opossum using the surfactant benzyldimethyltetradecylammonium chloride (BAC). This study further characterizes the achalasia model. METHODS: BAC or saline was injected circumferentially into the LES of 14 adult opossums. Eight months after injection, manometry, isolated muscle bath studies, electrical field stimulation, and histochemical analysis were performed. RESULTS: Manometrically, the LES of BAC-treated opossums showed higher pressures (38.7 +/- 12 mm Hg vs. 17 +/- 3.0 mm Hg) and reduced esophageal body contraction amplitudes (4.2 +/- 3 mm Hg vs. 27.4 +/- 12 mm Hg). Isolated muscle strips challenged with carbachol and sodium nitroprusside contracted and relaxed similarly to controls. Electrical field stimulation failed to induce relaxation in BAC-treated tissue but did induce contraction. Contractile responses were markedly reduced by tetrodotoxin and atropine in BAC-treated animals and controls. An altered nitric oxide system was shown by the lack of response to L-arginine and N omega-nitro-L-arginine. Histology showed loss of myenteric neurons and increased cholinergic nerve bundles. CONCLUSIONS: Loss of NO inhibitory myenteric neurons markedly reduces the relaxation of the LES, and histology and pharmacological responses suggest a proliferation of cholinergic nerves into the LES contributing to the static elevated pressures of the amyenteric LES.

Effects of detomidine on equine oesophageal function as studied by contrast radiography.

The effects of sedation with detomidine on oesophageal function were assessed by contrast radiography in 10 healthy adult thoroughbred horses. Barium swallows were monitored by means of image intensification, first without sedation and then after the intravenous administration of detomidine at doses of 10 and 20 micrograms/kg bodyweight. The transit time of contrast agent to the oesophageal hiatus was recorded and each swallow was scored for markers of oesophageal dysfunction. Analysis of the data indicated that there were highly significant dose dependent increases in the transit time, the retention of barium within the longitudinal mucosal folds, and retrograde peristalsis and pooling of contrast agent within the oesophagus at both the thoracic inlet and caudal to the base of the heart. The degree of gastrooesophageal reflux was not affected at either dosage. These changes in oesophageal function were similar to those recorded from cases of grass sickness and indicate that care should be taken in the interpretation of studies of swallowing in animals that have been given detomidine before a radiographic examination.