Anatomy Of The Lower Esophageal Sphincter Biology Essay

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The gastrointestinal tract has four distinct functional layers: mucosa, submucosa, muscularis propria and adventitia. The mucosa contains 3 components. They are epithelium , lamina propia and muscularis mucosa.At the gastroesophageal junction, the mucosa of the tract undergoes an abrupt transition from a protective stratified squamous epithelium to simple columnar mucous secreting form which important to protect gastric wall from acid components.The sub mucosa contains loose collagen tissues, blood vessels, lymphatics and nerves. The layer of muscles called muscularis mucosa consists mainly 2 components. The muscular wall proper consists of smooth muscle that is usually arranged as an inner circular layer and an outer longitudinal muscle layers.(2)

The lower esophageal sphincter(cardiac sphincter) is a physiological sphincter. It is not distinct anatomical sphincter. It prevents the reflux of gastric components into esophagus. following mechanisms have been suggested by experimental and clinical evidences. these mechanisms play major and minor roles to prevent reflux of gastric components.(3)

1â-Šâ-ŠMucosal folds at the gastroesophageal junction act as a valve.(3)

2â-Šâ-ŠThe acute angle of entry of esophagus into stomach produces a valve like


3â-Šâ-ŠThe circular muscle of the lower esophagus act as physiological sphincter

(intrinsic sphincter)(1)

4â-Šâ-ŠThe arrangement of the muscle fibers of the stomach around the cardia

acts either as a sphincter or else maintains the acute angle of entry of

esophagus into stomach.(3)

5â-Šâ-ŠThe right crus of the diaphragm acts as a 'pinch-cock' to the lower

esophagus as it pierces this muscle.(extrinsic sphincter)(1)

6â-Šâ-ŠThe positive intra-abdominal pressure compresses the walls of the short

segment of intra-abdominal esophagus.(3)

however, new studies has suggested that the patients with barrett's esophagus were hyposensitive to heat and acid stimulations both in the metaplastic and normal parts of esophagus.

function of lower esophageal sphincter

LES has tonic activity that prevents the reflux of gastric components into esophagus between meals but relaxes when swallowing. The tone of LES under neural control. contraction of intrinsic is done by acetylcholine that release from vagal endings. release of NO & VIP from interneurons innervated by other vagal fibers causes it to relax. contraction of the crural portion of diaphragm which is innervated by the phrenic nerves is coordinated with respiration and contraction of chest and abdominal muscles.


diagnosis of barrett's esophagus in gastro esophageal reflux disease is done by using endoscopy test showing proximal displacement of the squamocoluminar mucosal junction and biopsies demonstrating intestinal metaplasia.This metaplasia may be seen as continual sheet or finger like projection extending upward from the squamocoluminar junction and or as island of columinar mucosa spread in areas of residual squamous mucosa.(4) Recent guidelines suggest recording the length of circumferential CLO (C measurement)as well as the maximum length (M measurement) to aid assessment of progression or regression. (4) The longitudinal extent and pattern of mucosal displacement is related to the severity of reflux.(5)

 Barrett's esophagus is a columnar metaplasia extend from the gastroesophageal junction that involves short (<3 mm) or long (>3 mm) regions of the esophagus is found respectively in 5% and 15% of patients, undergoing endoscopy for reflux symptoms. It is also often found rarely in endoscoped patients without reflux symptoms. Barrett's is commonest in middle-aged men. The major concern is that 0.5-1.0% of Barrett's patients develop oesophageal adenocarcinoma per year. Barrett's increases the chance of developing adenocarcinoma 30- to 50-fold.Progression of Barrett's to cancer occurs through increasingly worse grades of dysplasia. The dysplasia is patchy, and biopsies from all four quadrants (every 2 cm) of the Barrett's segment are recommended, as well as biopsies from macroscopically abnormal areas. High grade dysplasia (HGD) can be hard to differentiate from early adenocarcinoma and there is a high risk of progression. Indeed, 30-40% of patients with HGD have cancer in the resected specimen. Chromoendoscopy (the topical application of stains or pigments via the endoscope) magnification and narrow band imaging may aid the diagnosis of intestinal metaplasia, dysplasia and carcinoma.

Development of barrett's ulcers can be considered as a secondary complication. this ulcers resemble to gastric ulcers and frequently give rise to bleeding.(5)

Barrett's esophagus was diagnosed according to the guidelines of the American College of Gastroenterology.(6-807)

Estimation of accurate risk is very important economics surveillance and other interventions to prevent carsinoma in BE patients.


incompetence of lower esophageal sphincter causes reflux of gastric components into esophagus. in these conditions, intrinsic , extrinsic or both sphincters can be weak. these sphincter are controlled under neural drive.(1) gastroesophageal reflux is common condition causes heartburn and esophagitis and can leads to ulceration & stricture of esophagus due to scarring.(1)

In patients with gastroesophageal reflux diseases, the distal esophagus may become lined by columinar epithelium instead to normal stratified squamous epithelium.That resist to acidic components reflux from stomach. Reepithelilization is occured from immature pluripotent stem cells,which in microenvironment of low pH in distal esophagus lumen differentiate into gastric type. Small amounts of gastro-oesophageal reflux are normal.(4) In 1957 barrett referred to this morphological changers as lower esophagus lined by columinar epithelium. But this is more often referred to as barrett's esophagus. in this condition, the distal esophagus above the LES is lined by gastric type(columinar) epithelium.(5) Although it can be rarely in origin. It is more often acquired condition and represents the long standing gastroesophageal reflux. It is a complication of severe gastro-oesophageal reflux disease due to severe LOS hypotension and there is almost always a hiatus hernia.(4) . The major concern is that 0.5-1.0% of Barrett's patients develop oesophageal adenocarcinoma per year. Barrett's increases the chance of developing adenocarcinoma 30- to 50-fold.(4).  


The development of barrett's esophagus mainly contains 2 steps.

1.transformation of normal esophageal mucosa to simple columnar epithelium

this is relatively quick and occurs within few years

2.the development of goblet cells

this procedure is relatively slow and occurs probably over 5-10 years.

Adenocarsinoma of esophagus

Cancer is the common term for almost any malignant tumor. when A malignant tumor arising from epithelium, it is called carcinorma. The term denocarsinoma can be considered as further classification of carcinorma, arising from glandular epithelium.(2)

Adenocarsinoma of esophagus more often found in middle or lower third. some of more distally located tumors can be extend into stomach. The risk of developing esophargeal adenorcarsinoma is 30-40-fold higher in patients with Barrett's esophagus (BE) compared with the general population(6 -459a). The development of EAC in BE has been shown to occur through a multistep process of increasing grades of epithelial dysplasia, from no dysplasia to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and finally EAC. (6 -459a) This entire process is commonly described as the Barrett's metaplasia-dysplasia-carcinoma sequence.(6)This timescale gives the opportunity to early detect neoplastic progression and prevent progression to incurable EAC. Adenorcarsinoma have been estimated to account for between 5-10% of all esophageal cancers.(5)

Esophageal adenocarsinoma is increased in western countries and marginal survival rate is not still changed during last 30 years. This is despite the introduction of new endoscopic techniques.(6) Barrett's esophagus mirrors the appearance and progression of gastric Intestinal metaplasia to gastric adenocarcinoma common in Asia.Cellular Origin of Barrett's Metaplasia

 The dominant concept for the origin of Barrett's esophagus is the acid reflux damages the esophageal squamous epithelium, thereby exposing multipotential stem cells in the basal layers to refluxed gastric juice that stimulates abnormal differentiation. Transition of  human esophageal epithelial cells to Barrett's esophagus have employed bile salts and low pH of gastric fluids.

One recent study has suggested that circulating stem cells of bone marrow origin might contribute to the development of Barrett's esophagus, Although the progenitor cell for Barrett's esophagus remains unknown. metaplasias must arise from changes in cellular gene expression.

acid and bile induce the expression of caudal homeobox genes such as CDX1 andCDX2.the meaning of homeobox is a shifting in structural development.

 homeobox genes encode transcription factors that regulate cell differentiation during embryogenesis. In adult cells, alterations in homeobox genes might alter cellular phenotypic features.  Homeobox gene expression in adult cells can be regulated epigenetically, such as through alterations in gene promoter methylation, or via cell signaling pathways regulated by factors like bone morphogenetic proteins (BMPs) or fibroblast growth factors.

Compared to normal esophageal squamous epithelium, BMP4 expression is increased in Barrett's metaplasia; in a rat model of reflux-induced Barrett's esophagus, BMP4 expression is increased in the stroma that underlies the Barrett's metaplasia. Cultures of human esophageal squamous cells treated with BMP4 express cytokeratins that are characteristic of columnar cells. Bile acids, at neutral and acidic pH levels, cause a cancer cell line to express CDX2 through ligand-dependent transactivation of the epidermal growth factor receptor. It was therefore proposed that GERD induces the expression of Cdx genes through BMP4 and, perhaps, EGFR activation, and that GERD-induced Cdx expression might partially mediate the development of Barrett's metaplasia.


RISK FACTORS of barrett's esophagus

As found in Western countries, advancing age, hiatus hernia and probably GERD, appear to be among the major risk factors for BE in the Chinese population. All except for one study showed a slightly male predominant distribution in BE In a population study on patients reporting for annual health check-up.

Abuse of tobacco and alcohol and metabolic disorders appeared to be risk factors In a prospective study in Taiwan.

The research showed that hiatal hernia and GERD duration of over 5 years were independent risk factors for BE with ratios of 4.7 and 4.2, respectively in china.

 Increasing severity of gastroesophageal reflux disease was associated with the decreasing prevalence of Helicobacter pylori.(6)

Central obesity increases the risk of Barrett's by 4.3times(4)


According to the World Health Organization definition, any tumor that crosses the GEJ, regardless of where the bulk of the tumor lies, is classified as a GEJ cancer. This group of cancer cells may originate from the distal esophagus or the proximal stomach. Many recent studies in western countries show that a similar profile between barrett's esophagus related adenocarsinoma and adenocarsinoma of proximal stomach in epidemiollgy, clinical presentation, molecular biology, and pathology.

Age- and Gender-Specific Yield of Barrett's Esophagus by Endoscopy Indication

according to the analysed data of the National Endoscopic Database of the Clinical Outcomes Research Initiative (CORI), They have  found a substantial increased yield for Barrett's esophagus in middle adulthood compared to early adulthood among white men with GERD,  with a plateau in yield after approximately age 50. there fore metaplasia is taken place between 20-50 ages in most patiens. Another important finding was found by endoscopy test with women with GERD. in women younger than age of 30, no patients ware found with barrett's esophagus in a large study.  Remarkably, we found that older white women with GERD were no more likely to have Barrett's esophagus than white men without GERD.(6)

The new studies  have shown that Barrett's segment length was greater in men than in women(6) & Women were less likely to have HGD or cancer than men.


Barrett's esophagus itself does not cause symptoms. The reflux of acid that causes Barrett's esophagus often leads to symptoms of heartburn. However, many patients with this condition do not have symptoms.

Tests for barrett's esophagus

After seeing the symptoms of GERD or symptoms have come again, after the patients have been treated, the doctors may do an endoscopy.

endoscopy-A thin tube with small camera is inserted through the mouth, then passes through the esophagus to stomach. while doing the endoscope, the doctor can get biopsies in different parts of esophagus.

Treatments of GERD

treatment should be focus on acid reflux symptoms, and may keep barrett's esophagus without getting worse. treatment may involve life style changers and medication as below

Antacids after meals and at bedtime

histamine H2 receptor blockers

proton pump inhibitors

and anti-reflux surgery.

Most patients are treated with lifelong proton pump inhibitors. that is effective in symptoms control. however, they have ability to prevent complications but, neither benign nor malignant can be controlled in clinical practice.

Most studies which based on outcome of reflux control have shown that drugs or antireflux surgery are relatively short term.  acid suppression with proton pump inhibitors is more effective than H2 receptor antagonist.


Surgery or other procedures may be recommended if a biopsy shows cell changes that are very likely to lead to cancer. Such changes are called severe or high-grade dysplasia.

Some of the following procedures remove the harmful tissue in your esophagus, where the cancer is most likely to develop.

Photodynamic therapy (PDT) uses a special laser device, called an esophageal balloon, along with a drug called Photofrin.

Other procedures use different types of high energy to destroy the precancerous tissue.

Surgery removes the abnormal lining.


Diagnosis and treatment for GERD may prevent the barrett's esophagus.



Erosive esophagitis occurs along with BE. as well as, with GERD patients without BE. new finding shows that esophagitis occurs in 19% of BE patients.


they occur within the distal esophagus near the squamocolumnar junction.


the development of ulceration within the columnar lined segment occurs up to 60% cases. it may be present with complication such as bleeding, more rarely, with perforation into meadiastinum or fistula formation.


During the development of adenocarcinoma there is a gradual increase in dysplastic features of the epithelium through LGD and HGD culminating in invasive cancer.