Barrett’s Esophagus

Barrett’s esophagus is a chronic gastroesophageal reflux disease Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease) that leads to the replacement of stratified squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium with gastric columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium in the esophagus. The condition is associated with an increased risk of esophageal adenocarcinoma. Workup includes an esophagogastroduodenoscopy (EGD) showing proximal displacement of the squamocolumnar junction (Z-line) from the gastroesophageal junction (GEJ). Biopsies will confirm the diagnosis by revealing columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium and goblet cells in the distal esophagus. Treatment is primarily with proton pump inhibitors (PPIs) and lifestyle modifications. Surveillance with repeated EGD and biopsy is necessary to monitor for early signs of dysplasia.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Epidemiology and Etiology

Epidemiology

  • Incidence: approximately 1%–10% in the United States
  • Mean age is approximately 55 years.
  • Men are more commonly affected.
  • More prevalent in whites

Etiology

  • Gastroesophageal reflux disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease)
    • Erosive esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis
    • Peptic stricture
    • Hiatal hernia
  • Smoking: has a synergistic effect with GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease
  • Central obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
  • Family history
  • Oral bisphosphonates Bisphosphonates Bisphosphonates are pyrophosphate analogs most well-known for treating osteoporosis by preventing bone loss. Bisphosphonates end in the suffix "-dronate" or "-dronic acid" (e.g., alendronate, risedronate, pamidronate) and bind to hydroxyapatite crystals in bone, inhibiting osteoclast-induced bone resorption. Bisphosphonates

Pathophysiology

Mucosal injury

  • Chronic reflux of gastric acid
    • pH
    • Duration of exposure
  • Compromised protection mechanisms
    • Antireflux barrier 
      • Lower esophageal sphincter (LES)
      • Extrinsic compression of the diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm
    • Clearing mechanism
      • Gravity
      • Bicarbonate secretion from esophageal and salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands
      • Peristalsis
    • Epithelial defense factors to resist acid entry into intercellular spaces
      • Thick epithelial layer
      • Tight junctions
      • Lipid-rich intercellular space

Metaplasia

  • Occurs when 1 type of differentiated tissue replaces another
  • Adaptive response to injury
  • Mechanism:
    • Erosion of mucosa → inflammatory cell infiltration → epithelial necrosis
    • Repair of damaged esophagus → replacement with columnar cells
      • Transdifferentiation of squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium into columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium
      • Potential migration of progenitor or residual embryonic from gastric cardia or gastroesophageal junction

Dysplasia

  • Acid and bile salts → oxidative DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage in epithelial cells → cell proliferation and abnormal development
  • Likely also a genetic component
  • Patients are at risk for esophageal adenocarcinoma.
Barrett's esophagus metaplasia

Barrett’s esophagus metaplasia.
Schematic demonstrating the development of metaplasia after injury to the esophageal epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium in Barrett’s esophagus. There are several proposed mechanisms.
A: Repair of reflux-induced injury leads to transdifferentiation of esophageal epithelial cells.
B: Repair of damaged tissue results from progenitor cells of the gastric cardia.
C: Repair of damaged tissue results from residual embryonic cell migration from the gastroesophageal junction or gastric cardia.

Image by Lecturio.

Clinical Presentation and Diagnosis

Clinical presentation

  • Patients present with symptoms associated with GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease and its complications.
    • Heartburn
    • Regurgitation
    • Dysphagia
    • Odynophagia
  • Physical exam is generally unremarkable.

Diagnosis

Screening:

  • Recommended in high-risk patients with GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease
  • Long-standing symptoms (> 5 years)
  • Age > 50 years
  • Smoking history
  • Obesity
  • First-degree relative with esophageal adenocarcinoma
  • Screening of the general public is not recommended.

Esophagogastroduodenoscopy (EGD):

  • Procedure of choice
  • Gross findings:
    • Evidence of columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium
      • Erythematous distal esophagus
      • Velvet or “ tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue”-like texture
      • Squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium is usually pale and glossy.
    • Squamocolumnar junction (Z-line, where columnar and squamous epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium meet in the esophagus) 
      • ≥ 1 cm above the gastroesophageal junction (GEJ) 
      • Irregular border
  • Biopsy findings:
    • Required for diagnosis
    • Columnar epithelium Epithelium The epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions. Surface Epithelium
    • Goblet cells (mucin-secreting cells, seen in the intestinal mucosa)
    • Gastric foveolar-type cells (mucin-secreting glands, normally seen in the gastric mucosa)

Management and Complications

Management

Management goal is to treat underlying acid reflux to decrease the risk of cancer development.

  • Proton pump inhibitors (PPIs)
    • Preferred over H2-receptor blockers
    • Treatment is indefinite.
    • Common choices:
      • Omeprazole
      • Pantoprazole
  • Diet modifications, aiming to avoid:
    • Fatty foods
    • Acidic foods and drinks
    • Caffeine 
    • Alcohol
    • Eating prior to bedtime
  • Avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Weight loss

Surveillance and dysplasia management

  • The intention is to detect dysplasia and adenocarcinoma early so that treatment can be initiated promptly.
  • Involves repeated EGD and biopsy sampling:
Endoscopy biopsy findings Management
Barrett’s esophagus (metaplasia only) PPIs and EGD every 2–3 years
Low-grade dysplasia PPIs and EGD every 6–12 months
High-grade dysplasia Endoscopic ablation or resection (endoscopic or surgical)
Increasing diagnostic accuracy to grade dysplasia in barrett's esophagus

Hematoxylin and eosin staining of esophageal mucosal biopsies.
A: non-dysplastic Barrett’s mucosa characterized by uniform, bland nuclei arranged in a surface monolayer
B: low-grade dysplasia exhibiting nuclear hyperchromasia, elongation, and stratification extending up to the surface epithelium Surface epithelium Epithelium is classified according to the cells (squamous, cuboidal, columnar), the number of layers, and other unique characteristics either due to function (transitional epithelium allowing distention) or appearance (pseudostratified epithelium giving a false impression of multiple layers). Surface epithelium has multiple functions, which include protection, secretion, filtration, and sensory reception. Surface Epithelium
C: high-grade dysplasia depicting increased architectural and cytologic complexity, including loss of nuclear polarity
D: intramucosal adenocarcinoma characterized by severe architectural distortion, including angulated glands. (a–d, 100×)

Image: “Increasing diagnostic accuracy to grade dysplasia in Barrett’s esophagus” by Karamchandani DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, Lehman HL, Ohanessian SE, Massé J, Welsh PA, Odze RD, Goldblum JR, Berg AS, Stairs DB. License: CC BY 4.0

Complications

Esophageal adenocarcinoma is the most significant morbidity.

  • Uncommon overall
  • Helicobacter Helicobacter Helicobacter pylori is a gram-negative bacterium that causes gastric infection. It is the most well known and clinically significant species of Helicobacter. Transmission is believed to occur by ingestion of contaminated food or water; therefore, a higher prevalence of infection is seen in areas with poor sanitation. Helicobacter pylori infection is actually protective.
  • Requires referral to oncology
  • Management depends on staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis and the patient’s overall health.

Differential Diagnosis

  • Esophageal adenocarcinoma: a malignant tumor of the distal esophagus. Barrett’s esophagus, obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, and smoking are risk factors for this malignancy. Patients may present with dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, regurgitation, and weight loss. Esophagogastroduodenoscopy and biopsy will help diagnose and differentiate this from Barrett’s esophagus. Management is based on staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis and the overall health of the patient but may include surgical resection, radiation, and chemotherapy.
  • Esophageal squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma: a malignant tumor of the middle esophagus. Risk factors include smoking and alcohol. Symptoms are similar to esophageal adenocarcinoma and include dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, regurgitation, and weight loss. Esophagogastroduodenoscopy and biopsy will establish the diagnosis and differentiate it from Barrett’s esophagus. Treatment depends on staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis and the patient’s overall health but includes surgical resection, radiation, and chemotherapy.
  • Eosinophilic esophagitis Esophagitis Esophagitis is the inflammation or irritation of the esophagus. The major types of esophagitis are medication-induced, infectious, eosinophilic, corrosive, and acid reflux. Patients typically present with odynophagia, dysphagia, and retrosternal chest pain. Esophagitis: a chronic, immune-mediated condition of the esophagus, which leads to esophageal dysfunction. Symptoms include heartburn, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, and food impaction. Esophagogastroduodenoscopy and biopsy will show strictures, stacked circular rings, linear furrows, and eosinophil-predominant inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, differentiating this condition from Barrett’s esophagus. Management includes an evaluation of food allergies, PPIs, and topical glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids.
  • Gastroesophageal reflux disease ( GERD GERD Gastroesophageal reflux disease (GERD) occurs when the stomach acid frequently flows back into the esophagus. This backwash (acid reflux) can irritate the lining of the esophagus, causing symptoms such as retrosternal burning pain (heartburn). Gastroesophageal Reflux Disease): a condition caused by reflux of gastric contents into the esophagus, which can lead to irritation and erosion. Gastroesophageal reflux disease is a precursor to Barrett’s esophagus. Symptoms include heartburn, dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming "stuck." Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, and nausea. Diagnosis is usually clinical, but those with severe symptoms or risk factors may require EGD. This can help differentiate it from Barrett’s esophagus. Treatment includes lifestyle modifications and PPIs.

References

  1. Spechler, S.J. (2020). Barrett’s esophagus: Epidemiology, clinical manifestations, and diagnosis. UpToDate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/barretts-esophagus-epidemiology-clinical-manifestations-and-diagnosis
  2. Spechler, S.J. (2020). Barrett’s esophagus: Pathogenesis and malignant transformation. UpToDate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/barretts-esophagus-pathogenesis-and-malignant-transformation
  3. Spechler, S.J. (2020). Barrett’s esophagus: Surveillance and management. UpToDate. Retrieved November 2, 2020, from https://www.uptodate.com/contents/barretts-esophagus-surveillance-and-management
  4. Johnston, M.H., and Eastone, J.A. (2017). Barrett esophagus. In Roy, P.K. (Ed.), Medscape. https://emedicine.medscape.com/article/171002-overview

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