Barrett’s esophagus is the condition in which a specialized columnar epithelium replaces the normal stratified squamous epithelium of the esophagus. Prolonged acid injury to the squamous epithelium can cause this metaplastic change in about 10% to 15% of individuals suffering from gastroesophageal reflux disease (GERD). This specialized columnar epithelium serves a protective function, as it is more resistant to the stomach acid. However, it also increases the risk of esophageal adenocarcinoma. There is a good correlation between the rising incidence of adenocarcinoma of the esophagus with the increasing incidence of GERD. Therefore, timely evaluation and treatment of patients with GERD for Barrett’s esophagus are important.
Barrett's metaplasia occurs as a result of prolonged tissue injury in the esophagus due to chronic gastroesophageal reflux disease (GERD). One of the risk factors of GERD and its complications has been the increase in obesity, especially central adiposity. The underlying mechanism may be linked to an increase in intra-abdominal pressure as well as elevated serum levels of pro-proliferative hormones. Cigarette smoking is a risk factor for both Barrett's metaplasia and esophageal adenocarcinoma, but the association with alcohol is weak.
There are two large case-control studies of twins suggesting that the development of Barrett's esophagus in GERD is genetically predisposed.
Other studies have proposed the decreasing prevalence Helicobacter pylori infection in western populations as a contributing factor for the development of Barrett's esophagus and resultant dysplastic changes. The lack of acid secretion in chronic atrophic gastritis associated with H. pylori infection may have been protective against GERD.
Barrett's esophagus is seen in about 10% to 15% of individual with GERD. It is discovered during endoscopic examinations done for evaluation of GERD or other indications. It mainly affects middle-aged, and older adults and the average age at diagnosis is approximately 55 years. The condition is prevalent in white men, and for unclear reasons, fairly uncommon in African Americans and Asian populations. The prevalence of Barrett's esophagus ranges between 1.6% to 6.8 % in western societies.
The estimated risk for esophageal cancer in patients with Barrett's esophagus ranged between 0.2% to 2.9%. The highest risk is found in patients with high-grade dysplasia followed by low-grade dysplasia. Malignant transformation in non-dysplastic Barrett's esophagus is low.
Multiple pathophysiologic mechanisms predispose to a reflux diathesis in patients with Barrett's esophagus. A decrease in the lower esophageal sphincter pressure increases the reflux of both acidic and bile in the distal esophagus. The presence of a hiatal hernia can serve as a pocket for gastric acid, increasing distal esophageal acid exposure. Ineffective esophageal motility and gastric acid hypersecretion are also potential causes of increased esophageal acid exposure. Frequency and interplay of these mechanisms differ among patients.
Animal studies suggested that transcommitment is the principal pathogenic mechanism in Barett's esophagus. Transcommitment highlighted how the esophageal stem cells that normally differentiate into squamous cells differentiate into abnormal columnar cells in response to injury. Subsequently, circulating bone marrow stem cells were shown as precursors of Barrett's epithelium. Most recently, migration of cells from the gastric cardia have been shown to be responsible for metaplasia of the distal esophagus. However, the true mechanism of metaplastic change is still unknown.
On gross examination, the abnormal columnar epithelium is described classically as salmon colored with a velvet-like texture, in contrast to the pale and glossy squamous epithelium of the distal esophagus. Based on the endoscopic appearance, Barrett's esophagus can be classified as long-segment (the metaplastic segment extends at least 3 cm above the esophagogastric junction) or short-segment (when it is limited to less than 3 cm of the distal esophagus).
Histologically, intestinal metaplasia with goblet cells is pathognomonic for Barrett's esophagus and carries pre-malignant potential. Some experts have suggested that gastric cardia type epithelium above the esophagogastric junction as evidence of metaplasia with malignant potential. This observation remains to be proven.
Barrett's cells, by accruing genetic mutations, become dysplastic (also called as intraepithelial neoplasia), before final transformation into adenocarcinoma. Histologically, cells are recognized as dysplastic if they demonstrate lack of cytoplasmic maturation, crowding of tubules or nuclear changes such hyperchromatism, stratification and atypical mitoses.
Dysplasia can be classified into low-grade dysplasia (LGD) and high-grade dysplasia (HGD) depending on the degree of abnormalities, with a high-grade representative of more severe changes. Two expert pathologists should confirm the histopathology of LGD and HGD. Any dysplasia increases the risk of progression into adenocarcinoma of the esophagus. Once diagnosed they should be recommended to be ablated or resected.
Barrett's metaplasia itself does not cause any symptoms. Patients typically present with a history of long-standing heartburn, regurgitation or dysphagia, symptoms typical for GERD. In patients who have symptomatic GERD, long segment Barrett's esophagus is found in 3% to 5% and around 10% to 20% have short segment disease. Increased severity of underlying GERD is associated with an increased incidence of Barrett's metaplasia.
Diagnosis of Barrett's esophagus is made on upper endoscopy. During the exam, the endoscopist must first ascertain the esophagogastric junction (EGJ) marked by the proximal extent of the gastric folds. Patients are suspected to have Barrett's metaplasia if an abnormal looking salmon-colored mucosa is seen extending above the EGJ into the distal esophagus. Classically it has been categorized into long or short segment disease. An international working group developed a grading system of Barrett's esophagus, the Prague C and M criteria which recognizes the circumferential and maximal extent of the metaplastic epithelium. It has high overall validity for endoscopic assessment of Barrett's esophagus. However, the clinical value of the system is yet to be established. Therefore, patients are managed by the same principles, irrespective of the length of Barrett's metaplasia.
A four-quadrant random biopsy sampling technique is employed, and biopsies are obtained every 2 cm, throughout the length of visible Barrett's metaplasia. Areas of dysplasia most often have no visible endoscopic changes, are patchy, and therefore there does exist a substantial sampling error. Many endoscopic techniques have been developed in recent years including narrow band imaging or chromoendoscopy to enhance the detection of dysplasia. These multimodal endoscopic techniques are promising; however, more clinical information is needed to inculcate them in regular practice.
As GERD is the principal pathophysiological mechanism for Barrett’s disease, its treatment forms a crucial aspect of management. Lifestyle modifications such as weight reduction, smoking, and alcohol cessation, the dietary modification including avoiding bedtime snacks and head-of-the-bed elevation using 6 to 8-inch blocks are all important nonpharmacological approaches to management of GERD. Although dietary modification including smoking cessation is commonly advised, only weight loss and elevation of the head of the bed have been associated with improvement of GERD in case-controlled studies.
Proton pump inhibitors are the most effective agents against GERD and its complications. As a rule, they should be used in the lowest effective dose. In patients with Barrett’s esophagus, they are used for the initial and maintenance therapy independent of the presence of esophagitis. Some patients with Barrett’s disease may become asymptomatic without normalization of esophageal acid exposure. This may be due to their inherent predisposition to reflux. Fundoplication had been suggested as a more effective means for reducing distal esophageal acid exposure and thus decrease the incidence of cancer in these patients. However, multiple studies including one randomized controlled trial have debunked this notion.
Aspirin and other NSAIDs have been proposed as chemoprotective agents against the development of adenocarcinoma in patients with Barrett's esophagus. This data is based on in-vitro and animals based studies. Epidemiological studies have also shown a decreased risk of esophageal adenocarcinoma with NSAID use. Serious gastrointestinal (GI) and cardiovascular side effects associated with NSAIDs may outweigh potential benefits. Therefore, routine use of these drugs is not recommended.
Although endoscopic screening for all patients with GERD without risk factors has not been found to be cost-effective, it should be considered if more than one risk factor is present. These risk factors include age 50 years or more, white, male gender, obesity, especially central adiposity, tobacco use, or a long duration of reflux symptoms.
Utility and benefit of endoscopic surveillance for dysplasia in patients with Barrett's esophagus have been a contentious issue due to a lack of randomized control trial showing a mortality benefit, an overall low incidence of esophageal adenocarcinoma in patients with Barrett's metaplasia, and financial expense of interval endoscopies. Given the low risk of endoscopic procedures, the theoretical efficacy of surveillance measures preventing cancer, observational and computer models demonstrating the benefit of surveillance, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy and American College of Gastroenterology recommend endoscopic surveillance for dysplasia in patients with Barrett's esophagus.
If no evidence of dysplasia is found, the surveillance endoscopy is recommended every 3 to 5 years. If dysplasia is noted, then usually another endoscopy is recommended for extensive sampling to rule out invasive cancer. This is to minimize the sampling error inherent in the procedure. Expert pathology review, usually by more than one pathologist, is needed due to the inherent difficulty in differentiating between reflux esophagitis and low-grade dysplasia. Once low-grade dysplasia (LGD) has been confirmed, follow up surveillance endoscopy is recommended in 6 to 12 months although endoscopic eradication therapy is an acceptable alternative after discussing the risks and benefits with the patients. If high-grade dysplasia (HGD) is detected, without evidence of invasive carcinoma, endoluminal therapy for eradication of visible Barrett's metaplasia is strongly recommended.
Endoscopic eradication therapies have become the mainstay of treatment for patients with Barrett’s esophagus with dysplasia. This can be achieved using application of heat through laser, radiofrequency, argon plasma coagulation, cold through cryotherapy or photodynamic therapy (PDT) to destroy the abnormal epithelium. Due to comparable efficacy and beneficial side effect profile, radiofrequency ablation is the preferred mode of endoscopic therapy compared to PDT. Cryotherapy can be substituted depending on local expertise. Ablation therapies are indicated for flat lesions. Any nodular lesions should be removed using endoscopic mucosal resection, which also provides a substantial sample for determining the depth of invasion. Endoluminal therapy is not recommended in cases of submucosal invasion because it is associated with much higher risk of metastatic spread.
Esophagectomy was previously the treatment of choice for high-grade dysplasia and intramucosal carcinoma in Barrett's disease. It is associated with prolonged hospital stay, short and long-term complications with a poor quality of life in the immediate post-op period and therefore is no longer the first line treatment. It can be considered on an individual basis in patients with high-grade dysplasia or carcinoma-in-situ if endoluminal therapy is not feasible or unable to eradicate the neoplastic disease.