2.2.1

Population-Based Studies/Routine Endoscopy

In population-based studies, the overall prevalence of BE in general population varied between 1.6% and 6.8% in western countries . In a study by Gerson et al. , a 25% BE prevalence rate was noted in male veterans older than 50 years of age. In another study, both men and women above age 65 years undergoing screening colonoscopy were requested to undergo routine upper endoscopies after completing a detailed GERD questionnaire. Overall prevalence of BE was 16.7% and symptoms of heart burn were not significantly associated with BE .

2.2.2

Patients with Chronic Gastroesophageal Reflux Disease

Prevalence rates of BE in patients with symptomatic GERD are somewhat higher than in the general population with rates of 13–20% . Long segment BE is found in 3–5% and short segment BE in 10–15% .

2.2.3

Autopsy Studies

Many individuals with BE remain undiagnosed. In one of the few autopsy-based studies, Cameron et al. found a prevalence rate of 376 cases per 100,000 in Olmsted County, Minnesota, which was 21-fold higher than the clinically recognized cases in the county.

2.2.4

Geographic Variation

There is considerably more data on the prevalence of BE in western countries as compared to Asian countries. In general, the prevalence rates were higher in the western hemisphere compared to Asia. Two large prospective studies investigated the prevalence of BE in Japan and found an overall prevalence of BE of 0.9–1.2% . The prevalence rate of BE in China from a pooled analysis of reports from 1989 to 2007 was 2.4% . In South America, the prevalence rate of BE was 3.57% among patients with GERD symptoms .

2.4.1

Gastroesophageal Reflux Disease

Though initially described as a congenital condition, BE had become widely accepted by the 1970s to be an acquired condition associated with severe GERD . Since then, epidemiologic studies have confirmed that GERD is indeed the most important risk factor for BE. A recent meta-analysis showed that there is a threefold increased risk of BE with GERD (odds ratio (OR) 2.90, 95% confidence interval (CI), 1.86–4.54, p =0.0001) and almost fivefold increased risk for long segment BE (OR 4.92, 95% CI 2.01–12.0, p =0.30) . BE patients are also more likely to have frequent reflux symptoms, nocturnal GERD, and longer duration of symptoms than controls . It is not only the chronicity and severity of symptoms but also younger age of onset of symptoms that seem to increase the risk of BE in GERD .

Several physiologic mechanisms contribute to severe GERD in patients with BE ( Table 2.1 ). Studies show a strong correlation between the abnormal and prolonged esophageal acid exposure and development of BE. In 1994, Neumann and Cooper demonstrated that BE patients had longer duration of esophageal acid exposure and higher number of reflux episodes of greater than 5 min when compared with reflux esophagitis patients. In another study, compared to the patients with esophagitis, patients with BE had lower median lower esophageal sphincter (LES) pressure (10.5 vs 17.5 mmHg; p =0.013) and higher median percentage of total time with pH less than 4 (48.2 vs 8.7 and 23.2 vs 5.2; p =0.0001 for distal and proximal esophageal acid exposure, respectively) . Duodenogastroesophageal reflux is a major contributing factor to the development of BE. Also, the pattern of acid and/or bile exposure seems to play a role in that only persistent exposure led to the development of columnar epithelium in contrast to short exposure .

The exact molecular pathways leading to the development of BE in GERD are not well elucidated. Chronic reflux of acid and bile can lead to BE by several mechanisms such as (1) oxidative DNA damage due to production of free radicals and nitric oxide , (2) inflammatory cytokine production by recruitment of immune cells such as naive T cells, macrophages, and dendritic cells into the esophagus, (3) deregulation of microRNAs which are short noncoding RNAs involved in a variety of cellular processes (eg, miRNA-145 was linked to the activation of BMP4 pathway which promotes squamous-to-columnar metaplasia), (4) express CDX2 (a gene known to play a key role in the development of intestinal epithelia) and MUC2 (a mucin normally found in intestinal goblet cells), and (5) decline in esophageal squamous progenitor cells as evidenced by reduction in p63 protein levels in esophageal cell cultures (a marker for squamous progenitor cells) .

Two major hypotheses have been proposed to explain the cellular origin of Barrett’s metaplasia. As per the transdifferentiation theory, the cells in the esophagus that normally would differentiate into squamous cells instead differentiate into columnar cells triggered by surface epithelial damage from acid and bile . In contrast, the stem cell theory proposes that columnar metaplasia results from proliferation of stem cells which may originate from the basal cell layer of the squamous epithelium, gastric cardia, submucosal glands, or from the bone marrow .

GERD is the most prevalent gastrointestinal disorder with an estimated prevalence of 18–28% in North America. However, less than 10% of patients with GERD develop BE. This suggests that BE is a multifactorial disease and several factors other than GERD may play a role in an individual’s susceptibility for this condition. These contributing factors for BE are described in the following sections.

2.4.2

Age

Older age is a risk factor for BE although the age at which this risk increases is uncertain. Different population-based studies showed an increase in prevalence of BE from 30 to 70 years . There is a 1.3-fold increase in risk of BE with each additional decade of age (95% CI 1.02–1.67, p =0.03) . More recent studies reveal an increased risk of BE with early age at onset of GERD symptoms. There seems to be a linear association of age at onset of GERD symptoms and risk of BE independent of the duration of GERD symptoms ; however, more studies are required to validate these results as there may be other risk factors such as childhood obesity, hiatus hernia, and genetic factors contributing to BE.

2.4.3

Gender

BE is thought to be a disease predominantly occurring in men. The risk of BE among men with GERD symptoms is 1.5- to 3-fold higher than that of women . Several theories including differences in parietal cell mass, differences in LES function, and higher body mass index (BMI) among males have been proposed to explain the protective effect against the development of BE in women . Women also seem to develop BE at a later age compared to men. This age shift leads to a lower prevalence of BE in females compared to the male population, with 2:1 male to female sex ratio . This age lag seen in women explains to some extent the marked gender-based differences that are also seen in EAC as men have BE earlier in their lives and have more time to develop dysplasia and EAC.

2.4.4

Race

BE is far more common in Caucasians compared to other ethnic groups. In an observational study from Kaiser Permanente in California, the prevalence of BE among non-Hispanic whites was twofold higher compared to Hispanic whites (247 vs 135/100,000 years, respectively, p <0.01) and approximately fivefold higher than among blacks as shown in Fig. 2.1 (49/100,000 years, p <0.01) . Similarly, an endoscopy study from the United Kingdom showed an increased risk of BE among Caucasians compared to Asians (OR 6.03, CI 3.56–10.22) . One plausible reason for higher prevalence of BE in Caucasians may be increased reflux of acid and a reduction in esophageal clearance leading to more severe GERD . Studies assessing BE in the Hispanic population show no increased prevalence with 10% among Latinos and 12% among non-Latino whites, respectively .

Prevalence of Barrett’s esophagus by year of diagnosis and ethnicity, 1994–2006.

A large database study of 280,075 endoscopic procedures showed that BE was found most often in whites (5% vs Hispanic 2.9% vs black 1.5%, Asian/Pacific islander 1.8%; p <0.0001). Although the racial distribution of the database appeared to be similar to the Centers for Medicare and Medicaid Services (CMS) database, caution must be taken in generalizing the results of this study due to the inherent limitations of any large database such as risk of misclassification, as race group was entered by provider and not the patient, and the diagnosis of BE was made on endoscopic visualization without histologic confirmation .

2.4.5

Family History of Barrett’s Esophagus or Esophageal Adenocarcinoma

Approximately 7% of the BE patients have a family history of BE or EAC . Patients with familial BE were younger at onset of reflux symptoms and at EAC diagnosis compared to nonfamilial BE suggesting genetic factors contributing to the pathogenesis of BE . Patients with BE are more likely to have first- or second-degree relatives with BE compared to normal population without BE (OR 12.2, CI 3.3–44.7) . New susceptibility genes for BE have been identified as two large genome-wide analysis studies reported genetic variants in BE . In the recent genome-wide study, Levine et al., after pooling data from 15 studies, identified genetic variants at three loci—CRTC1, FOXP1, and BARX1—that were significantly associated with BE and EAC. The inherited susceptibility to cancer appeared to be more related to early development of BE rather than progression of BE to EAC, emphasizing the need to understand the mechanisms/pathways that lead to the development of BE.

2.4.6

Visceral Obesity

Obesity is a well-known risk factor for GERD and EAC and possibly for BE. In a population-based case–control study, obese individuals with symptoms of acid reflux had markedly higher risk of BE (OR 34.4, 95% CI 6.3–188) than people with reflux alone (OR 9.3, 95% CI 1.4–62.2) or obesity alone (OR 0.7, 95% CI 0.2–2.4) . However, data on whether BMI is an independent risk factor for BE are not robust. Earlier studies evaluating obesity in BE that used patients with normal upper endoscopy as controls suggested a significant association of BMI with BE . However, subsequent large systemic reviews and meta-analyses did not find any significant risk of BE in patients with elevated BMI especially after adjusting for GERD; it was concluded that BMI was an indirect risk factor for BE through the precursor lesion caused by GERD .

Recent literature is supportive of visceral obesity, instead of BMI, as an important risk factor for BE. In a meta-analysis, abdominal obesity, measured by visceral adipose tissue area on abdominal CT, waist–hip ratio, or waist circumference, was significantly associated with BE independent of GERD (OR 1.98, CI 1.52–2.57 for greatest vs lowest category of abdominal obesity) . Factors other than increased intra-abdominal pressure from the mechanical effects of obesity may play a role. Intra-abdominal fat is a metabolically active tissue producing adipokines such as adiponectin and leptin which have effects on cellular proliferation, apoptosis, angiogenesis, and inflammation, and are associated with increased risk of BE.

In contrast to abdominal obesity that is associated with BE, gluteofemoral obesity may have a protective effect in BE. In a study by Rubenstein et al. , each 5 cm increment in hip circumference was associated with 13% decreased risk of BE (OR 0.87, CI 0.76–0.99). Although several theories based on positive association of gluteofemoral obesity with insulin sensitivity and adiponectin levels have tried to explain the protective effect of gluteofemoral obesity, it is not clear how gluteofemoral obesity exerts a protective effect on BE. It is postulated that nonabdominal subcutaneous adipose tissue acts as a “metabolic sink” for nonesterified fatty acids thereby offering protection against their deleterious metabolic effects. This may explain the lower prevalence of BE in women in spite of their higher volumes of nonabdominal subcutaneous adipose tissue.

2.4.7

Smoking

The association between smoking and BE is unclear. Cigarette smoking is a strong risk factor for EAC and was long considered a traditional risk factor for BE. Being a potentially modifiable risk factor, several studies examined the association of smoking with BE. The strongest evidence of smoking as a risk factor for BE came from a pooled analysis from five case–control studies within the BEACON Consortium—an international Barrett’s and Esophageal Adenocarcinoma Consortium—that found people with BE to be more likely to have ever-smoked compared to population-based controls (OR 1.67, CI 1.04–2.67) or compared to GERD controls (OR 1.61, CI 1.33–1.96). Moreover, the association was dose responsive with increased association seen up to 20 pack-years when it began to plateau . This association of smoking with BE was further confirmed by a recent meta-analysis where having ever-smoked was associated with increased risk of BE compared to non-GERD controls (OR 1.44, 1.20–1.74) and GERD controls (OR 1.42, 1.15–1.76) . On the contrary, in one large case–control study on BE in the United States where a systematic collection of detailed smoking data was obtained, Thrift et al. demonstrated smoking as not being a strong risk factor for BE. Similar results were noted by other investigators and it is speculated that the increased susceptibility of smokers to Helicobacter pylori might explain a protective effect against BE .

2.4.8

Alcohol

Excessive alcohol consumption may increase esophageal reflux, cause inflammation, and lead to carcinogenesis. Several studies showed a significant association of heavy alcohol ingestion and esophageal squamous cell carcinoma . However, the evidence on alcohol causing EAC and its precursor BE is limited. Recent studies have shown no association of alcohol intake and BE. A pooled analysis of individual patient data from multiple case–control studies, which included 1169 cases with BE, 1282 population-based controls, and 1418 GERD controls, found no association between BE and alcohol .

2.4.9

Diet

Diet is a modifiable risk factor for BE. However, only limited studies have evaluated the association of dietary intake and risk of BE, most of which are case–control studies. Although studies have shown inverse risk between BE and fruit and vegetable intake , this association is not consistent across all studies with a few studies reporting no association . Two large population-based case–control studies in the United States have reported an inverse association ; in one study within the Kaiser Permanente northern California population where cases with BE ( n =296) were matched with GERD controls ( n =308) and population controls ( n =309), there was an inverse association of fruit and vegetable intake and BE. Subjects in the fourth quartile of fruit and vegetable consumption were 73% less likely to have BE when compared to first quartile . However, this inverse association was not seen when compared to GERD controls suggesting that patients with GERD may not benefit in terms of risk of BE from increased intake of fruits and vegetables. In the second study, a similar inverse association was seen between fruit and vegetable intake and the risk of BE . A study from Ireland reported similar findings with 40% reduction in BE risk among subjects with greater than 34 portions of fruits and vegetables per week, compared to those with less than 20 portions per week . Authors hypothesize that fruits and vegetables contain antioxidants that are believed to suppress oxidative stress and decrease carcinogenesis . Yet there is no strong evidence to support the protective effect of antioxidants intake and BE. Studies have failed to show any effect of antioxidant intake such as vitamin C, vitamin E, selenium, supplemental vitamins, or beta carotene level on the risk of BE .

Fiber intake has been inversely linked to the risk of BE . Fiber intake is hypothesized to absorb carcinogens from food that pass through gastrointestinal tract and reduce risk of BE .

2.4.10

Diabetes Mellitus

There is sparse data studying diabetes mellitus (DM) as a risk factor for BE. A population-based study of over 8 million subjects found a significant association between BE and DM. Patients with BE (14,245 subjects) were matched with controls (70,361 subjects); and after adjusting for known risk factors such as obesity, smoking, and GERD, patients with BE were twofold more likely to have diabetes compared to controls (OR 2.03, CI 1.2–3.6) . Being a case–control study, it is difficult to prove causation and more prospective studies are required to understand the link between BE and diabetes. The postulated mechanism of esophageal injury in diabetes involves activation of insulin-like growth factor pathway that promotes tissue proliferation through activation of the phosphoinositol-3-kinase/AKT/mammalian target of rapamycin pathway and other similar pathways that lead to cell proliferation .

2.4.11

Obstructive Sleep Apnea

Recent studies have demonstrated obstructive sleep apnea (OSA) as a risk factor for BE independent of obesity and GERD. It has been hypothesized that a more negative intrathoracic pressure due to OSA can lead to increased nocturnal reflux and possibly weakening of the LES leading to the development of BE . This is further supported by the fact that improvement in GERD is seen following the use of continuous positive airway pressure for OSA in several studies . Furthermore, patients with OSA are more likely to be obese which predisposes them to a hiatal hernia, increasing the risk of acid reflux and prolonged exposure to gastric acid . In a recent case–control study at the Mayo Clinic, patients with OSA had 80% increased risk of BE as compared to patients without OSA (OR 1.8, 95% CI 1.1–3.2), and this association was independent of other risk factors .

2.4.12

Erosive Esophagitis

Untreated erosive esophagitis is considered to be a risk factor for BE. In a recent prospective Swedish study, Ronkainen et al. reported erosive esophagitis as a significant risk factor for BE (relative risk ratio (RR) 5.2, CI 1.2–22.9) and found 8 new cases of BE after following 90 cases of erosive esophagitis for 5 years.

2.4.13

Hiatal Hernia

Patients with BE have larger hiatal hernias than those without BE . It is hypothesized that a hiatal hernia lowers LES pressure, increases the propensity to reflux, and therefore increases the risk of BE . A recent meta-analysis of 4390 BE patients revealed a significant association of hiatal hernia and BE (OR 3.94, CI 3.02–5.13), and this association remained significant in subgroup analyses even after adjusting for clinically important confounders such as obesity and GERD .

2.4.14

Helicobacter pylori

One of the causes attributed to the increasing incidence of EAC and BE is the declining prevalence of H. pylori infection. H. pylori causes atrophic gastritis and the resulting reduction in parietal cell mass leads to less acid production. Therefore, GERD, erosive esophagitis, and BE are less likely to occur. However, the studies regarding the effect of H. pylori on BE are inconsistent. A recently published meta-analysis of 49 studies showed that H. pylori infection, especially with cag A strains, is protective against BE (RR, 0.46, 95% CI 0.35–0.60) .