Gastroesophageal reflux disease (GERD) is the overarching term for a constellation of upper GI conditions that cause symptoms such as heartburn, chest pain, dry cough and regurgitation. In the case of laryngopharyngeal reflux, extraesophageal symptoms, including dyspnea, hoarseness, chronic sore throat and enlarged pharyngeal tonsils may manifest in the absence of heartburn.

GERD occurs in 15-20% of the North American population. It is even more common in the UK, Iceland, Pakistan, Turkey, Argentina; and the highest incidence is found in India, Greece, Romania and Poland. A meta-analysis found that the male/female sex ratio was 1.57 for erosive esophagitis, 0.72 for NERD and 1.96 for Barrett’s esophagus.¹

Barrett’s can progress further into dysplasia or adenocarcinoma, but a large majority do not progress. Short segment Barrett’s is the term for metaplasia that is less than 3 cm in length. Long segment Barrett’s is defined as tongues of metaplastic change extending more than 3 cm from the gastroesophageal junction. There is a seven-fold increased risk of progression from Barrett’s to high grade dysplasia or adenocarcinoma in long segment vs short segment Barrett’s. For each additional cm in length there is an increase of 19% risk of progression.

The irritative effects found when gastric and/or duodenal contents (bile) reflux into the lower esophagus can take various forms. The most minor is non-erosive reflux disease (NERD) in which no gross changes are seen during an upper endoscopy exam. In erosive esophagitis gross erosions are seen. Over time—with the chronic inflammation from these processes—a metaplastic change in the lining cells can lead to Barrett’s esophagus (BE). In Barrett’s the esophageal mucosa is attempting to adapt to the continued inflammation. If there is continued progression the next stage is mild, moderate, or severe dysplasia. The rarest and final stage is esophageal adenocarcinoma.

It is important to realize that chronic heartburn symptoms are not always present in those who develop Barrett’s or esophageal adenocarcinoma (EAC). EAC may occur de novo. To quote a review article by Katzka DA in 2020,

Moreover, even though BE increases the risk of EAC, that is a rare outcome and BE is not associated with a measurable decrement in life expectancy. Furthermore, only a small fraction of EAC patients are observed to progress through the classical sequence of erosive esophagitis, BE, dysplasia, cancer… In fact, in a landmark Scandinavian population-based epidemiology study 40% of EAC patients reported no prior history of frequent heartburn and 38% had no identifiable BE at the time of resection or autopsy. Confirming this, a subsequent large study reported that approximately half of prevalent EACs presented without BE or reflux symptoms.

In addition, patients diagnosed with EAC who do not have concurrent Barrett’s metaplasia have a poorer prognosis than those with Barrett’s.² This suggests that the metaplasia may be an adaptive response. There is evidence that a mix of bile and acid reflux may be especially potent for driving the progression of Barrett’s to esophageal cancer.³

An important finding is that most patients with reflux have dilated intercellular spaces (DIS), which appears to be the esophageal version of “leaky gut syndrome.” It is most severe in Barrett’s esophagus.⁴ It is considered a non-specific finding because it is also found in other esophageal diseases and in 30% of “healthy” subjects.⁵ DIS is not reported on an esophageal biopsy report because it is so common and requires electron microscopy to elucidate such detail. It has been well described in the literature.⁶

Sex-Based Risk Factors, Clinical Manifestations, and GERD

The patient’s sex is a major factor determining the progression, or lack of progression in GERD. Significant independent risk factors for reflux esophagitis in women include age over 70 years, obesity, hypertriglyceridemia, central obesity (waist circumference > 33.5 inches), current smoking status, and hiatal hernia. Women experience more heartburn, regurgitation, and extra-esophageal symptoms (ie cough, hoarseness). They also have a higher incidence of non-erosive disease. After age 70, women have increasing incidence of erosive esophagitis—prior to this age it is significantly less common than in men.

Significant independent risk factors for reflux esophagitis in men include overweight or obese habitus, hypertension, hypertriglyceridemia, central obesity (waist circumference >40 inches), current or past tobacco smoking, excessive alcohol consumption, and hiatal hernia. For men, age does not appear to be a significant risk factor. Males are more likely than females to develop Barrett’s, Barrett’s with dysplasia, and esophageal adenocarcinoma.

A British endoscopy study found that both men and women have a 7% increase in development of Barrett’s esophagus over a lifetime. For men this increase starts at age 20, but in women it is delayed until age almost age 40. This 17-year age lag causes a 3.5:1 male predominance for Barrett’s.⁷ Large Dutch and Irish studies found similar results.^8,9 Another reports that the male predominance is 4:1 for younger patients and 2:1 when all ages are included. It appears that women experience more symptoms of GERD but develop Barrett’s later in life and likely will die from other causes before developing esophageal adenocarcinoma. This correlation may be in part due to a protective anti-inflammatory effects of estrogen. Some studies suggest that other confounding factors may include gender differences in alcohol and tobacco consumption.

Estrogen

Research suggests that estrogen may increase esophageal mucosal resistance. The mechanism appears to be up-regulation of esophageal tight junction protein expression such as occludin. A study of male rabbits found that 17β-estradiol administration reduced the risk of dilated intercellular spaces in response to various esophageal irritants. These rabbits also had increased expression of occludin, which may be the reason that estrogen administration was able to increase mucosal cellular adhesion and protect against esophagitis. The reduced protective effects of estrogen in men may be one of the factors that cause a higher prevalence of reflux esophagitis in men than in women.¹⁰ The higher levels of estrogen in women prior to menopause may explain the decreased prevalence of reflux esophagitis in women and the increase after age 50. Estrogen may also be delaying the onset of Barrett’s esophagus and esophageal cancer.

In addition, a Swedish population-based study of over 200,000 women suggests that hormone replacement therapy for women has a protective effect against esophageal adenocarcinoma. It also reduced the odds ratio for developing esophageal squamous cell carcinoma and gastric carcinoma. Both estrogen-only hormone replacement and combination estrogen and progestin therapy were significantly protective in all age groups.¹¹ Anti-inflammatory action and support for esophageal epithelial resistance against refluxate could be associated with the sex differences found in GERD.

Histamine/Mast Cell Activation

Preliminary studies of mast cell activity and GERD have been limited to non-human research. Yu et al have shown that mast cell tryptase increases the sensitivity of sensory nerves and induces long-lasting hyperalgesia in guinea pigs.¹² Intraepithelial T lymphocytes and mast cells have been demonstrated in mucosal biopsies of GERD patients, giving at least an entry for further research into mast cells in the pathogenesis.¹³ In functional GI disorders mast cells are an important regulator of neuro-immune human barrier function.¹⁴ Oral ketotifen, both a mast cell membrane stabilizer and H1-receptor antagonist, has been found to reduce symptoms of visceral perception in IBS patients.¹⁵ An in vivo study of healthy volunteers showed normalization of increased small intestinal permeability by pre-treatment with the mast cell stabilizer cromolyn sodium.¹⁶ Stabilizing mast cells to restore barrier function in both NERD and functional GI disorders seems a reasonable target for further study. In a study of 413 mast cell activation syndrome subjects Lawrence Afrin et al wrote that “Gastroesophageal reflux, fatigue, and dermatographism were the most common comorbidity, symptom, and exam findings.”¹⁷

Options for Periodic Monitoring of Barrett’s Esophagus (BE)

Patients with non-dysplastic Barrett’s are 10 times more likely to die from an unrelated cause than cancer.¹⁸ A meta-analysis of 57 studies found an annual esophageal cancer risk of 0.33% for Barrett’s. “Patients with a short segment of BE and who have had two consecutive endoscopies demonstrating gastric metaplasia only should be discharged from surveillance as their cancer risk is 1:1400 years of follow-up.”¹⁹ The Mayo Clinic does not recommend endoscopic monitoring for women with short segment Barrett’s.²⁰ The sponge capsule (Cytosponge) is a newer less-expensive and less-invasive method of screening for dysplasia and adenocarcinoma designed for primary care settings:

The sponge capsule is a pill approximately the size of a multi-vitamin that is attached to a string. Compressed inside the capsule is a spherical sponge. Once the capsule is swallowed, it dissolves in approximately 5 minutes, and the sponge emerges. After 5 minutes, a nurse pulls the sponge out by the string and stores the sponge in a standard specimen container with preservative at room temperature. The specimen can then be sent to a laboratory using standard transport. The sample is stable in a refrigerator and can be kept for several weeks before processing, if necessary.²¹

Options for Reversing or Halting the Progression of Barrett’s

The best practice advice from the American College of Gastroenterology²² includes the statements:

1. Patients with GERD and acid-related complications (ie. Erosive esophagitis or peptic stricture) should take a PPI for short-term healing, maintenance of healing, and long-term symptom control.

• Patients with Barrett’s esophagus and symptomatic GERD should take a long-term PPI.
• Asymptomatic patients with Barrett’s esophagus should consider a long-term PPI

Research on acid suppression and Barrett’s is mixed. A meta-analysis found a 71% reduction in the risk of high-grade dysplasia and adenocarcinoma, while a Danish population-based study with over a decade of follow-up found that the subjects with the best compliance taking PPIs had the highest risk of esophageal adenocarcinoma.²³ A 2017 meta-analysis concluded that “no dysplasia or cancer-protective effects of PPI usage in patients with BE were identified by our analysis. Therefore, we conclude that clinicians who discuss potential chemopreventative effects of PPIs with their patients, should be aware that such an effect, if it exists, has not been proven with statistical significance.”²⁴

My Key Objectives

Treat prediabetes and diabetes, reduce BMI, support smoking cessation, and reduce or eliminate alcohol consumption. Treat other underlying causes of reflux (for details see Getting Real About Reflux, which I am writing currently and expect to publish in 2022).

• Control or correct reflux (by treating the cause when possible)
• Prevent dysplasia in areas of metaplasia
• Increase differentiation of epithelium
• Promote healing of the esophagitis
• Maintain MnSOD, catalase, glutathione, and vitamin E. MnSOD expression is significantly decreased as Barrett’s progresses to esophageal adenocarcinoma.²⁵

Additional Nutritional Supports for Barrett’s Healing

Increased intake of vegetables and fruits is associated with a lower risk of Barrett’s in men and women.²⁶ Berry extracts preserve MnSOD expression.²⁵

Green tea catechins. Polyphenon E (in green tea extract) inhibits the growth of transformed epithelial cells and suppresses cyclin D1 leading to cell cycle arrest.²⁷

Selenium slows cell growth, prevents DNA damage and facilitates apoptosis in p53 deficient cancer cells. In Barrett’s patients. Higher selenium levels were associated with a decreased risk of later stages of progression such as high-grade dysplasia and aneuploidy and may prevent inactivation of p53.²⁸

Tumeric. In a rat model, curcumin effectively prevented acute reflux esophagitis and was more effective than lansoprazole (PPI) in inhibiting a mix of acid and bile reflux.²⁹

Vitamin E and overall antioxidant nutrient intake– higher intake of vitamin E from food and supplements combined was associated with decreased risk of esophageal adenocarcinoma. A combination score of multiple antioxidants has proven to have a consistently negative association with esophageal adenocarcinoma risk.³⁰

References

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9. Coleman HG, et al. Increasing incidence of Barrett’s oesophagus: a population-based study. Eur J Epidemiol. 2011.
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14. Wallon C, et al. Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitro, Gut. 2008;57:50-58
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16. Vanuytsel T, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014;63:1293-1299
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20. 7^th Annual Mayo Clinic Esophageal Diseases Course, Phoenix, Arizona 2019
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22. Freedberg DE, Kim LS, Yang Y-X. The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association. Gastroenterology. 2017 Mar;152(4): 706-715.
23. Hvid-Jensen F, et al. Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett’s oesophagus: a nationwide study of 9883 patients. Aliment Pharmacol Ther. 2014 May;39(9):984-91.
24. Hu Q, et al, Proton Pump Inhibitors Do Not Reduce the Risk of Esophageal Adenocarcinoma in Patients with Barrett’s Esophagus: A Systematic Review and Meta-Analysis. PLoS One. 2017; 12(1):e0169691.
25. Schiffman SC, Li Y, Martin RCG. The association of manganese superoxide dismutase in Barrett’s esophageal progression with MnTBAP and curcumin oil therapy. Journal of Surgical Research. 13 Dec 2011, 176(2):535-541
26. Thompson OM, et al, Vegetable and fruit intakes and risk of Barrett’s esophagus in men and women. Am J Clin Nutr. 2009 Mar; 89(2): 890-896.
27. Song S, et al, Polyphenon E inhibits the growth of human Barrett’s and aerodigestive adenocarcinoma cells by suppressing cyclin D1 expression. Clin Cancer Res. 2009. Jan 15; 15(2): 622-631.
28. Rudolph RE, Vaugan TL, Kristal AR et al, Serum Selenium Levels in Relation to Markers of Neoplastic Progression Among Persons with Barrett’s Esophagus. J Natl Cancer Inst. 2003 May 21: 95(10): 750-757.
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