In 1953, Allison and Johnstone argued that the columnar organ was more likely esophagus because the intrathoracic region lacked a peritoneal covering, contained submucosal glands and muscularis propria characteristic of the esophagus, and could harbor islands of squamous cells within the columnar segment. In 1957, Barrett agreed and suggested that the condition that bears his name be referred to as "lower esophagus lined by columnar epithelium." For the next 2 decades, descriptions of the histology of BE varied considerably from acid-secreting, fundic-type epithelium to intestinal-type epithelium with goblet cells.
Finally, in 1976 Paull et al published a report on the histologic spectrum of BE in which they used manometric guidance for their biopsies. These patients had 1 or a combination of 3 types of columnar epithelium—a gastric fundic-type, a junctional type, and a distinctive type of intestinal metaplasia the investigators called "specialized columnar epithelium." This specialized intestinal metaplasia (SIM), complete with goblet cells, has become the sine qua non for the diagnosis of BE.
While the histologic lesion became clearly evident, the endoscopic definition of BE has continued to change over the past 25 years. Many people believed that the distal esophagus could contain a normal region of columnar mucosa. In addition, determining the exact location of the esophagogastric junction (EGJ) in patients with BE often is difficult. To avoid false-positive diagnoses, investigators selected arbitrary lengths of columnar-lined esophagus to establish a diagnosis for their studies. Eventually, community endoscopists embraced this practice and biopsy of this so-called normal distal columnar-lined esophagus was avoided.
The last 10 years have brought convincing evidence that SIM, the hallmark histologic lesion of BE, predisposes to dysplasia and cancer regardless of the endoscopic location. Thus, the definition of BE currently is the finding of SIM anywhere within the tubular esophagus.
Pathophysiology: BE is well recognized as a complication of gastroesophageal reflux disease (GERD). Patients with GERD who develop BE tend to have a combination of clinical features, including hiatal hernia, reduced lower esophageal sphincter (LES) pressures, delayed esophageal acid clearance time, and duodenogastric reflux (as documented by the presence of bile in the esophageal lumen). First understanding the pathogenesis of GERD is necessary to understand the relationship between GERD and BE. Esophageal defense mechanisms against the noxious substances in the refluxate include an antireflux barrier, an efficient clearing mechanism, and epithelial defense factors. The antireflux barrier is a high-pressure zone at the EGJ that is generated by tonic contraction of the LES coupled with extrinsic compression by the right crus of the diaphragm. The phrenoesophageal ligament, intra-abdominal location of the LES, and maintenance of an acute angle of entry into the stomach help to reinforce this barrier.
This system is imperfect due to the existence of physiologic transient LES relaxations (TLESR). TLESR occur primarily after meals but in the absence of a preceding swallow. Studies indicate that about 95% of reflux episodes in healthy controls occur during the TLESR. Most reflux in patients with GERD occurs via this same mechanism. The duration of esophageal acidification, and not the frequency, correlates best with presence of erosive esophagitis.
A healthy individual clears the esophagus through various means, including gravity, bicarbonate secretion from the salivary and esophageal glands, and peristalsis. Dysfunctional esophageal motility with failed or weak peristalsis is a contributing factor in 34-48% of patients with GERD.
An acid (pH <4)>+ into both cells and intercellular spaces. In addition, scattered submucosal glands in the distal esophagus that secrete bicarbonate and have an adequate blood supply to deliver bicarbonate and remove H+ help to maintain tissue acid-base balance.
The aggressors in the GERD battle reside in the refluxate. Mucosal injury depends on the pH of the refluxate and the duration of contact with the esophageal mucosa. Lower pH of the refluxate and extended contact with the esophagus increases the time required for intraesophageal pH to return to normal and increases the risk for mucosal injury.
Prolonged exposure of the esophagus to the refluxate can erode the esophageal mucosa, promote inflammatory cell infiltrate, and ultimately cause epithelial necrosis. This chronic damage is believed to promote the replacement of healthy esophageal epithelium with the metaplastic columnar cells, the cellular origin of which remains unknown. This likely is an adaptive response of the esophagus, which, if not for the increased risk of cancer, would have been beneficial. GERD symptoms and strictures are less common in the columnarized segment.
Interestingly, the features of GERD in relation to long-segment Barrett esophagus (LSBE >3 cm) and short-segment Barrett esophagus (SSBE <3>
Current clinical practice guidelines recommend screening for BE in patients with GERD when the patients have had long-standing symptoms (>5 y), especially in those older than 50 years.
Epidemiology
Distinction of BE on the basis of the length of columnar-lined mucosa, however, turns out not to be entirely arbitrary. Endoscopically, the columnar-lined esophagus has been divided into 2 entities, with each having different prognostic implications. Long-segment BE is the finding of SIM longer than 3 cm, while short-segment BE is anything less than 3 cm. When the EGJ and squamocolumnar junction (SCJ) are contiguous and SIM is discovered on biopsy below the SCJ, the condition is termed cardia-SIM. The average age of patients with BE is 55-65 years. More than 80% are white males, with some studies indicating a higher prevalence of smoking and alcohol intake.
The prevalence of LSBE in patients undergoing endoscopy for any clinical indication has been reported at 0.3-2% but is much higher, 8-20%, in patients with symptoms of GERD. A study conducted at the Mayo Clinic showed an autopsy prevalence about 17 times higher than a clinically matched population, suggesting that most cases of LSBE are asymptomatic and thus unrecognized. In patients undergoing endoscopy, the prevalence of SSBE ranges from 5-30%. The combined prevalence of SSBE and cardia-SIM is 7-8 times greater than LSBE, but the prevalence of dysplasia and cancer is much less.
Frequency:
- In the US: Cameron (1997) estimated the prevalence of LSBE in the general US population to be 376 cases per 100,000 population.
- Internationally: The frequency of BE internationally probably parallels that in the United States by ethnicity. It is most common in people who are white and is rare in individuals of African descent.
Mortality/Morbidity: The most significant morbidity associated with BE is the development of adenocarcinoma in the esophagus. The incidence of esophageal adenocarcinoma is rising faster than any other cancer in the United States. From 1926-1976, 4 large surgical series reported that only 0.8-3.7% of esophageal cancers were adenocarcinomas. From 1979-1992, this increased to 54-68%.
In 1991, Blot et al reported their findings in a review of data from the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. The incidence of esophageal adenocarcinoma in 1988-1990 was 3 times that in 1976-1978. In Olmstead County, Minnesota, Pera et al (1993) conducted a population-based study and found that the incidence of esophageal adenocarcinoma rose from 0.13 cases per 100,000 person-years in 1935-1971 to 0.74 cases per 100,000 person-years in 1974-1989. The incidence of adenocarcinoma of the cardia rose from 0.25 to 1.34 cases per 100,000 person-years in the same time period, an increase of more than 5-fold for both locations. Patients with LSBE have the greatest risk for development of dysplasia and adenocarcinoma of the esophagus.
Recent studies report the prevalence of dysplasia in LSBE at 20-35%, SSBE at 6-8%, and cardia-SIM at 0-6%, with the prevalence of adenocarcinoma being 7-15 times greater in LSBE versus SSBE and cardia-SIM. However, the total number of patients with SSBE and cardia-SIM is 7-8 times that of LSBE. Thus, even with a higher prevalence of dysplasia and cancer in the LSBE population, a greater total number of patients are likely to develop cancer from within the SSBE and EGJ-SIM group.
Race: BE primarily affects white people. It is rare in people of African ancestry, at this time.
Sex: BE is found in both men and women, with a 2:1 male-to-female ratio.
Treatment
Medical Care: The diagnosis of BE does not lead to specific therapy. Little evidence supports the assumption that antisecretory agents or antireflux surgery prevents the occurrence of adenocarcinoma or leads to regression of BE. Haag et al conducted a comprehensive MEDLINE search in 1999 to determine the effect of medical, surgical, and ablative therapy in producing regression of BE.
In the early-to-mid 1980s, histamine 2 (H2)-receptor antagonists were the most commonly prescribed agents for treatment of GERD. A number of studies were conducted with either cimetidine or ranitidine, and none documented regression of BE. In the late 1980s, proton pump inhibitors (PPIs) were introduced and proved to be much more efficacious at reducing gastric acid secretion. The supposition that better acid suppression could induce BE regression was met with optimism. Studies to date, however, have been inconclusive. Only 2 of 7 investigators demonstrated some regression. Most were unable to detect any regression, despite documentation of complete normalization of esophageal pH by pH testing.
Currently, the indication for medical therapy in BE is the same as that for GERD—control of symptoms and healing of esophageal mucosa. An important, as yet unanswered, question is whether abolishing acid completely with high-dose PPIs decreases the risk for adenocarcinoma of the esophagus and warrants the cost and possible adverse effects of this therapy.
In addition to acid, the reflux of pancreatic and biliary secretions into the esophagus has been implicated in the pathogenesis of BE. Because medications are effective only at reducing the acid component, surgical therapy may have an advantage. While studies have shown surgery to be efficacious in the control of GERD symptoms, the results regarding BE regression are inconclusive. No good evidence indicates that surgical therapy provides regression in BE. Thus, antireflux surgery is not indicated for eradication of BE, but it certainly is reasonable for appropriate patients who desire surgery for control of GERD symptoms.
- Barrett esophagus screening and surveillance
- The Practice Parameters Committee of the American College of Gastroenterology recommends that patients with long-standing GERD symptoms (>5 y), particularly those aged 50 years or older, have an upper endoscopy to detect or screen for BE. Once identified, patients with BE should undergo periodic surveillance endoscopy to identify histological markers for increased cancer risk (dysplasia) or cancer that is at an earlier stage and is amenable to therapy. Preliminary data suggest that surveillance endoscopy does just that. Still, esophageal cancer is an uncommon cause of death.
- In a cohort study of patients with BE not undergoing surveillance, only 2.5% of 155 patients died as a result of esophageal cancer, with a mean of 9 years follow-up. Patients with BE should be considered candidates for surveillance only if a potential to prolong life expectancy exists and only if they are eligible for therapy when dysplasia or early cancer is detected. Age and comorbidity are important factors to consider.
- The goal of surveillance is the detection of dysplasia or early cancer. Currently, dysplasia is the best histological marker for cancer risk. The appropriate surveillance interval is based on published data on the natural history of dysplasia and primarily is a function of the grade of dysplasia. Surveillance involves repeated upper endoscopy with systematic 4-quadrant biopsies at 2-cm intervals along the entire length of the segment of BE, with additional biopsy of any mucosal abnormalities.
- Patients with BE in whom dysplasia is lacking for 2 consecutive yearly endoscopies may be extended to follow-up at 3-year intervals. Patients with persistent low-grade dysplasia on repeat endoscopy should undergo surveillance every 6 months for 2 cycles; if no progression of disease is noted, surveillance may be extended to yearly follow-up. Management of high-grade dysplasia is more controversial.
- Observer variation is a problem in the grading of dysplasia, and the first step in management of a patient with high-grade dysplasia always is confirmation of the diagnosis by a pathologist who is an expert at reading esophageal biopsies. The surgical literature suggests that as many as 40% of patients who undergo esophagectomy for high-grade dysplasia have concomitant cancer in the resected specimen.
- Currently, 2 alternatives for management of high-grade dysplasia exist. One is surveillance endoscopy, with intensive biopsy at 3-month intervals until cancer is detected. The other is surgical resection.
- Because dysplasia and cancer are patchy and cannot be visualized endoscopically, the diagnosis is difficult with even the most intensive surveillance. Current research is focused on developing endoscopic techniques that would highlight dysplastic tissue to allow directed biopsy and also finding surrogate cellular markers and the like that might help predict which patients will develop cancer in the absence of biopsy-proven dysplasia.
- The goal of ablative therapy is to destroy the Barrett epithelium to a sufficient depth to eliminate the intestinal metaplasia and allow regrowth of squamous epithelium. A number of modalities have been tried, usually in combination with medical or surgical therapy because successful ablation appears to require an anacid environment.
- Human studies have been performed with photodynamic therapy (PDT), argon plasma coagulation (APC), multipolar electrocoagulation (MPEC), heater probes, and various forms of lasers, endoscopic mucosal resection (EMR), cryotherapy, and radiofrequency ablation. Ablative therapy remains largely investigational with the exception of PDT, which is approved by the Food and Drug Administration (FDA) for high-grade dysplasia only.
- PDT involves the use of a photosensitizing agent that accumulates in tissue and induces local necrosis by means of production of intracellular free radicals following exposure to light at a certain wavelength. Typically, a hematoporphyrin is used as the photosensitizing agent because it has a greater affinity for neoplastic tissue.
- Recently, 5-aminolevulinic acid (ALA), which induces endogenous protoporphyrin IX and has selectivity for the mucosa over deeper submucosal layers, also has been used. The results have been promising for regression of BE, as well as for treatment of dysplasia and superficial carcinoma.
- Overholt et al treated 100 patients, 73 with high-grade dysplasia and 13 with superficial adenocarcinoma. Ablation of BE with regeneration of squamous epithelium reportedly was accomplished in 75-80% of patients. Other studies have shown similar response rates, but Barrett epithelium beneath the superficial squamous layer has been observed, indicating that deeper-placed pluripotent cells may be preserved. Additionally, PDT is an expensive and time-consuming endeavor, and early use was complicated by esophageal stricture requiring dilation in 58% of patients.
- APC is a method of contact-free high-frequency current coagulation in which the burning of tissue stops as soon as the area is ablated. One recent study using high-power APC was reported to result in complete restoration of squamous mucosa in 33 out of 33 patients after a mean of 1.96 sessions. The major complication was chest pain and odynophagia, which occurred in 57.5% of patients and lasted 3-10 days. Only 3 patients experienced stricture, which was treated easily with dilation. Only 1 endoscopic, as well as histologic, recurrence was observed at 10.6-months mean follow-up, but this was in a patient with an ineffective Nissan fundoplication.
- Other studies have been less encouraging, with persistence of residual foci of Barrett epithelium under the neosquamous lining in 22-29%, and deep esophageal ulceration with massive bleeding, perforation, and even death has been reported.
- MPEC is a method in which the mucosa is ablated by direct contact with an electrocautery probe. Sampliner et al (1996) used this technique to treat 10 patients with LSBE, using half of the patient's own esophagus as an internal control. All 10 patients had the treated segment eliminated by visual and biopsy criteria at 6 months, with the untreated segment unchanged despite acid suppression. Treatment took an average of 2.5 sessions, and 5 patients had complications in 75 total sessions (2 transient odynophagia, 1 transient dysphagia, 1 chest pain, and 1 upper gastrointestinal bleed).
- Lasers have been used in numerous small studies for eradication of BE. Results were less consistent with this modality than those listed above. Studies that demonstrated full or partial regression endoscopically were confounded by the persistence of glandular elements beneath the neosquamous epithelium in as many as one third of cases.
- Relatively new to the scene of endoscopic ablation is balloon-based, bipolar radiofrequency ablation (Stellartech Research Coagulation System; BARRx, Inc, Sunnyvale, Calif). This technique requires the use of sizing balloons to determine the inner diameter of the targeted portion of the esophagus. This is followed by placement of a balloon-based electrode with a 3-cm long treatment area that incorporates tightly spaced, bipolar electrodes that alternate in polarity. The electrode is then attached to a radiofrequency generator and a preselected amount of energy is delivered in less than 1 second at 350 W.
- One of the newer ablative techniques is low-pressure spray cryoablation using liquid nitrogen pioneered at the author's institution.
- The components of the low-pressure spray cryoablation device are the following: liquid nitrogen tank; electronic console for monitoring and control of cryogen release; dual foot pedal for control of cryogen release and heating of the catheter; and the catheter, which is a multilayered, 7-9F, open-tipped catheter for spray of supercold nitrogen gas through an upper endoscope. The mechanism of injury is unique relative to the other ablative techniques. Cryoablation induces apoptosis, causes cryonecrosis at supercold temperatures (-76° to -158° C), results in transient ischemia, and can cause immune stimulation. The Barrett epithelium is resistant to apoptosis and, therefore, may be uniquely suited for treatment by cryoablation.
- A recent pilot study at the author's institution using cryoablation in BE with degrees of dysplasia ranging from no dysplasia to multifocal high-grade dysplasia achieved complete endoscopic reversal of BE in 78% of cases, with no subsquamous SIM or dysplasia at 6-month follow-up. These results will need confirmation at other institutions.
Medication
Treatment of BE should be the same as that of GERD. However, most authorities agree that it should be used with a proton pump inhibitor versus an H2-receptor antagonist due to the relative acid insensitivity of patients with BE.
Drug Category: H2-receptor antagonists -- These agents are reversible competitive blockers of histamine at the H2 receptors, particularly those in the gastric parietal cells, where they inhibit acid secretion. The H2 antagonists are highly selective, do not affect the H1 receptors, and are not anticholinergic agents.
| Drug Name | Ranitidine (Zantac) -- Inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which reduces gastric acid secretion, gastric volume, and hydrogen concentrations. Indicated in acid/peptic disorder, erosive esophagitis, gastrointestinal hypersecretion, mastocytosis, gastroesophageal reflux, peptic ulcer, and Zollinger-Ellison syndrome. |
|---|---|
| Adult Dose | 150 mg PO bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution in renal or liver impairment; CrCl <10> |
| Drug Name | Famotidine (Pepcid) -- Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations. |
|---|---|
| Adult Dose | 40 mg/d PO bid for 4-8 wk |
| Pediatric Dose | Not established; suggested dose is 1-2 mg/kg/d PO/IV divided q6h; not to exceed 40 mg per dose |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | If changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment |
| Drug Name | Nizatidine (Axid) -- Competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and hydrogen concentrations. |
|---|---|
| Adult Dose | 300 mg PO hs or 150 mg bid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment |
| Drug Name | Omeprazole (Prilosec) -- Decreases gastric acid secretion by inhibiting parietal cell H+ and K+ pump. |
|---|---|
| Adult Dose | 20 mg PO qd; up to 40 mg qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of itraconazole and ketoconazole; may increase toxicity of warfarin (increased plasma levels of warfarin are observed only with high doses) |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Bioavailability may increase in elderly people; adjust dose in hepatic impairment, half-life can increase as much as 4-fold |
| Drug Name | Lansoprazole (Prevacid) -- Inhibits gastric acid secretion. Used for as long as 8 wk to treat all grades of erosive esophagitis. |
|---|---|
| Adult Dose | 30 mg PO qd for 4-8 wk |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | May decrease effects of ketoconazole and itraconazole; may increase theophylline clearance |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Consider adjusting dose in liver impairment |
| Drug Name | Esomeprazole (Nexium) -- S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at secretory surface of gastric parietal cells. |
|---|---|
| Adult Dose | 20-40 mg PO qd |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Concurrent use with amoxicillin or clarithromycin may increase plasma levels of esomeprazole; may reduce absorption of dapsone; may increase levels of diazepam and GI absorption of digoxin; may decrease absorption of iron, ketoconazole, and itraconazole |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Symptomatic relief with PPIs may mask symptoms of gastric malignancy |
| Drug Name | Porfimer (Photofrin) -- Indicated to treat high-grade dysplasia in Barrett esophagus. Elicits a photosensitizing effect used in the photodynamic therapy (PDT). |
|---|---|
| Adult Dose | 2 mg/kg IV infused over 3-5 min; may repeat treatment courses separated by at least 30 d, not to exceed a total of 3 treatment courses |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity to porphyrins; tracheoesophageal or bronchoesophageal fistula; tumors eroding into a major blood vessel |
| Interactions | Allow sufficient time between radiotherapy treatment to ensure inflammation has decreased; coadministration with other photosensitizing agents (eg, tetracycline, sulfonamides; hypoglycemic agents, thiazides) may increase photosensitivity risk; coadministration with drugs that inhibit oxygen species or free radicals (eg, DMSO, beta-carotene, ethanol, mannitol), allopurinol, calcium channel blockers, glucocorticoids, or prostaglandin synthesis inhibitors may decrease effect |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Use extravasation precautions; treatment-induced inflammation may obstruct main airway or cause chest pain; esophageal varices (increases bleeding risk); ocular sensitivity; monitor for respiratory distress |
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