Introduction
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 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.[1][2][3][4]
Etiology
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 and 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 of 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.[5]
Epidemiology
Barrett's esophagus is seen in about 10% to 15% of individuals 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 race males, 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 ranges between 0.2% to 2.9%. The highest risk is found in patients with high-grade dysplasia. Malignant transformation in non-dysplastic Barrett's esophagus is low.[6][7][8]
Pathophysiology
Multiple pathophysiologic mechanisms predispose to a reflux diathesis in patients with Barrett's esophagus. A decrease in the lower esophageal sphincter tone 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. The 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, the migration of cells from the gastric cardia has been shown to be responsible for metaplasia of the distal esophagus. However, the true mechanism of metaplastic change is still unknown.
Histopathology
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 is evidence of metaplasia with malignant potential. This observation remains to be proven.
By accruing genetic mutations, Barrett's cells become dysplastic (also called intraepithelial neoplasia) before final transformation into adenocarcinoma. Histologically, cells are recognized as dysplastic if they demonstrate a lack of cytoplasmic maturation, crowding of tubules, or nuclear changes such as 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.
History and Physical
Barrett's metaplasia itself does not cause any symptoms. Patients typically present with a history of long-standing heartburn, regurgitation, or dysphagia, which are symptoms typical for GERD. In patients with 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.
Evaluation
The 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 of having 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, known as the Prague C and M criteria, which recognizes the circumferential and maximal extent of the metaplastic epithelium. It has high overall validity for the 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.[9][10]
Once Barrett's esophagus is identified, 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 usually do not have visible endoscopic changes. Histologically, they are patchy in nature, and therefore there is a substantial sampling error for the biopsies. Many endoscopic techniques have been developed in recent years, including narrowband 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.
Treatment / Management
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, alcohol cessation, and dietary modifications, including avoiding bedtime snacks and keeping the head of the bed elevated using 6 to 8-inch blocks, are all important nonpharmacological approaches to the management of GERD. Although lifestyle modifications, including smoking cessation, are commonly advised, only weight loss and elevation of the head of the bed have been associated with improvement of GERD in case-controlled studies.[11][12][13]
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 adenocarcinoma development 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, caucasian race, 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 trials 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 another endoscopy is usually 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 the application of heat through laser, radiofrequency, argon plasma coagulation, cold 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 a 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-operative period, and 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.
Differential Diagnosis
The differential diagnosis of Barrett's esophagus includes esophageal diseases along the same spectrum of Berrett's metaplasia. These include:
Staging
Endoscopically Barrett's esophagus is classified into short-segment (≤3 cm) or long-segment (>3 cm) disease.
The Prague classification further categorizes the endoscopic lesion based on the degree of circumferential disease (noted by the letter C and a number indicating the length in centimeters) and the degree of esophagus segment length extending proximally (noted by the letter M and a number indicating the length in centimeters). A lesion noted to be Prague classification of C3M2 would mean that the Barrett esophagus extends circumferentially for 3 cm above the squamocolumnar junction and has "tongues" of Barrett esophagus extending 2 cm above the squamocolumnar junction.
Prognosis
Most patients with Barrett's esophagus do not progress to esophageal cancer. The reported progression to adenocarcinoma is estimated at approximately 0.5% annually in patients without dysplasia.[14] Treatment and surveillance are offered to all patients with Berrett's esophagus, based on the degree of dysplasia and the individual's risk factors, as described above, to minimize this risk of progression.
Complications
There are not any specific complications of Barrett's esophagus per se. The clinicians fear its progression to esophageal adenocarcinoma as the main complication and aim to prevent this development.
Deterrence and Patient Education
Patient education plays a vital role in the treatment of Berrett's esophagus. In addition to compliance with reflux therapy, they must be educated on the importance of lifestyle changes to prevent its progression to severe disease. Smoking cessation, alcohol avoidance, and weight loss therapy are essential changes that the patient must adapt to improve their outcome. Although multiple sources advise specific dietary changes, none have been linked to improved symptoms or prognosis. Most important in regards to dietary modification is the reduction in portion size. Limiting portion size, avoiding eating 3 hours before sleeping, and reducing weight have been shown to improve clinical outcomes in Barrett's metaplasia.
Enhancing Healthcare Team Outcomes
Treatment of Berrett's metaplasia and prevention of its progression to adenocarcinoma requires a multifaceted approach. It requires an interprofessional team of clinicians, nurses, pharmacists, and dieticians to collaborate to improve patient care and outcomes.
The nurse's role lies in assisting the team by educating the patient about lifestyle modifications to prevent the progression of this disease. These include smoking cessation, weight loss, reduction in portion size, and elevation of the head of the bed while sleeping. Ensuring compliance with these modifications and informing the clinician when specific additional therapies are needed to help the patient achieve these goals will significantly improve the morbidity associated with this disease.
The pharmacists should ensure timely refill of proton-pump inhibitor medications and ensure the patient's other medications do not interfere with these drugs. The pharmacist is also charged with the task of educating the patient on the use of over-the-counter medications, especially nonsteroidal anti-inflammatory medications, to limit gastrointestinal complications in these patients. If the pharmacist identifies a specific need for analgesic medications or interference of other prescribed medications with these drugs, he/she should communicate these findings to the clinician so that alternative therapies may be advised.
The dietician's role lies in educating the patient on appropriate portion size and weight reduction therapy to help them achieve weight loss and minimize complications.
Only by working as a collaborative interprofessional team can we improve patient outcomes related to Barrett's esophagus and help decrease the incidence of esophageal adenocarcinoma.
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Disclosure: Dhruv Lowe declares no relevant financial relationships with ineligible companies.
Disclosure: Pujitha Kudaravalli declares no relevant financial relationships with ineligible companies.
Disclosure: Ronald Hsu declares no relevant financial relationships with ineligible companies.
