Which factors best predict the risk of developing BO?

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Which factors best predict the risk of developing BO?

Introduction

Risk factors for Barrett’s Oesophagus (BO) have been assessed in more than 50 studies. All of the studies have been observational, and the vast majority to date have been case-control studies of varying degrees of quality. Several features of study design are likely to have contributed to differences in effect estimates between studies, particularly the ways in which BO cases and controls have been defined and selected. For example, a small number of studies have recruited only newly diagnosed BO cases, whereas others have recruited patients known to have pre-existing disease (‘prevalent cases’). Similarly, important differences are likely to exist between population versus institutional controls, and between ‘disease-free’ versus ‘reflux controls’. Other features include the quality of exposure measurements, the methods of analysis and control of potentially confounding factors. These elements of study quality must be borne in mind when assessing the evidence base. Wherever possible, estimates from higher quality studies have been used in the summaries below.

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Risk factors for Barrett's Oesophagus

Reflux

There is consistent observational evidence that patients with long-segment BO are much more likely (up to ten-fold in some reports) to report a past history of frequent (more than weekly) gastro-oesophageal acid reflux (GOR) symptoms than population controls. A systematic review of six high-quality observational studies reported a summary odds ratio of 4.92 (95% CI 2.01-12.0) for long segment BO and 1.15 (95% CI 0.763–1.73) for short segment BO.[1]

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Obesity

The association between body mass index (BMI, a simple but crude measure of body mass adjusted for height) and risk of BO has been inconsistent across studies. Most studies have reported small, non-significant, positive associations. Measures of central adiposity (such as waist circumference, waist-hip ratio) and visceral obesity (such as computed tomography (CT) measures of abdominal fat) have been consistently reported to be significantly associated with moderately increased risks of BO. A pooled analysis of four population-based case-control studies comprising 1102 BO cases and 1400 population controls found no evidence of a significant association between BMI and the risk of BO. In contrast, that pooled analysis observed that persons in the highest versus the lowest quartiles of waist circumference had approximately 125% and 275% increases in the odds of BO among men and women, respectively (men OR 2.24, 95% CI 1.08 - 4.65; women OR 3.75, 95% CI 1.47 to 9.56). The associations with measures of central obesity persisted after adjusting for the confounding effects of BMI and gastro-oesophageal reflux.[2] Similarly, a meta-analysis of 15 studies reported a summary OR of 1.98 (95% CI 1.52-2.57) for measures of central adiposity associated with BO.[3]

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Smoking

Data from case-control studies consistently report risks of BO among smokers to be about 50-60% higher than non-smokers, after adjusting for other potentially confounding factors. A pooled analysis using primary data from five case-control studies (1059 BO cases, 1332 gastro-oesophageal reflux disease (GORD) controls, 1143 population controls) reported a summary odds ratio of 1.67 (95% CI 1.04-2.67) for ever versus never smoking when comparing BO cases to population controls, and OR 1.61 (95% CI 1.33-1.96) when compared to GORD controls.[4] Similarly, a systematic review and meta-analysis of 39 studies comprising 7069 BO patients reported a summary odds ratio of 1.42 (95% CI 1.15-1.76) for ever versus never smoking when comparing BO cases to population controls.[5]

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Male sex

A systematic review and meta-analysis of 32 studies providing a sex ratio for Barrett’s Oesophagus reported a summary ratio of 1.96 (95% CI 1.77-2.17). Although there was considerable heterogeneity in the magnitude of the ratio across studies (ratio ranges 1.08-4.43), all studies observed a male excess of BO.[6]

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Age

Population studies suggest that the probability of a new diagnosis of Barrett’s Oesophagus increases with age. A US community study reported that the incidence of new Barrett’s Oesophagus was 7 per 100,000 person-years for people 21-30 years and 31 per 100,000 person-years for people aged 61-70 years (adjusted for the different endoscopy rates at different ages).[7] Case-control studies estimate that the relative risk of diagnosis of Barrett’s Oesophagus increases by about 30% per decade above 40 years when compared against patients with a diagnosis of gastro-oesophageal reflux disease.[8]

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Helicobacter pylori

A limited number of case-control studies have conducted serological assays comparing the prevalence of anti-H pylori antibodies between BO cases and controls. These studies have typically reported risk reductions of about 50% for persons with evidence of past infection with H pylori.[9].[10]

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Alcohol

There is no evidence that alcohol consumption increases the risk of BO. At least three high-quality case-control studies[11][12][13] and one cohort study[14] have examined this factor in detail and all reported null findings.

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Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)

A very small number of observational studies have investigated possible associations between self-reported use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and risks of BO.[15][16] There was no evidence that regular users of aspirin or NSAIDs differed in their risks of BO from never users.

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Diet

There is no consistent evidence implicating any dietary or nutritional factors in altering a person’s risk of BO, however studies are few.

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Metabolic factors

A small number of observational studies have investigated possible associations between metabolic factors and risks of BO. Some studies have reported modest positive associations with high levels of insulin and leptin,[17][18] although findings are inconsistent across studies. Data for other factors (such as insulin-like growth factors) are scarce.

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Hiatal hernia

Hiatal hernias have been reported more frequently among patients with BO when compared against both patients with gastro-oesophageal reflux disease (GORD) (about a three-fold increased relative risk) and non-GORD controls (about a 13-fold increased relative risk).[19]

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Family history

A small number of studies has investigated the family history of patients with Barrett’s Oesophagus. These studies estimate that about 7% of patients with Barrett’s Oesophagus have a confirmed history of Barrett’s Oesophagus or oesophageal adenocarcinoma occurring in a first- or second-degree relative,[20] equating to a relative risk about 12-fold higher than GORD controls.

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Risk prediction tools for Barrett's Oesophagus

One study has developed a prediction tool to estimate the probability that a person has BO.[21] The tool included terms for age, sex, smoking status, body mass index, education, and frequency of use of acid suppressant medications (area under the ROC curve, 0.70; 95%CI, 0.66–0.74). The model had moderate discrimination in an external dataset (area under the ROC curve, 0.61; 95%CI, 0.56–0.66).

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Other factors

Clinical studies have identified associations with obstructive sleep apnoea, although associations have been inconsistent across studies and residual confounding by other factors (notably obesity) cannot be excluded.[22][23]

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Evidence summary and recommendations

Evidence summary Level References
Major risk factors for Barrett’s Oesophagus have been well characterised in population-based studies, and include age, male sex, history of frequent gastro-oesophageal acid reflux, abdominal obesity, smoking and family history. III-3, IV [1], [2], [3], [4], [6], [8], [20]
Evidence-based recommendationQuestion mark transparent.png Grade
Clinical assessment of a person’s future risk of Barrett’s Oesophagus should consider:

• Age

• Person’s sex

• History of gastro-oesophageal acid reflux

• Waist-hip ratio or other measures of central adiposity

• Smoking history

• Family history of oesophageal adenocarcinoma and/or Barrett's Oesophagus

B


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Issues requiring more clinical research study

  • What is the role of aspirin/NSAIDs in the development of BO, and is chemoprevention possible?
  • Are there any dietary factors that reduce the risk of BO?
  • Is the apparent protective effect of Helicobacter infection causal? If so, what are the implications for clinical management?

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References

  1. 1.0 1.1 Taylor JB, Rubenstein JH. Meta-analyses of the effect of symptoms of gastroesophageal reflux on the risk of Barrett's esophagus. Am J Gastroenterol 2010 Aug;105(8):1729, 1730-7; quiz 1738 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20485283.
  2. 2.0 2.1 Kubo A, Cook MB, Shaheen NJ, Vaughan TL, Whiteman DC, Murray L, et al. Sex-specific associations between body mass index, waist circumference and the risk of Barrett's oesophagus: a pooled analysis from the international BEACON consortium. Gut 2013 Jan 26 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23355549.
  3. 3.0 3.1 Singh S, Sharma AN, Murad MH, Buttar NS, El-Serag HB, Katzka DA, et al. Central Adiposity is Associated with Increased Risk of Esophageal Inflammation, Metaplasia, and Adenocarcinoma: a Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2013 May 21 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23707461.
  4. 4.0 4.1 Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan TL, et al. Cigarette smoking increases risk of Barrett's esophagus: an analysis of the Barrett's and Esophageal Adenocarcinoma Consortium. Gastroenterology 2012 Apr;142(4):744-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22245667.
  5. Andrici J, Cox MR, Eslick GD. CIGARETTE SMOKING AND THE RISK OF BARRETT'S ESOPHAGUS: A SYSTEMATIC REVIEW AND META-ANALYSIS. J Gastroenterol Hepatol 2013 Apr 23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23611750.
  6. 6.0 6.1 Cook MB, Wild CP, Forman D. A systematic review and meta-analysis of the sex ratio for Barrett's esophagus, erosive reflux disease, and nonerosive reflux disease. Am J Epidemiol 2005 Dec 1;162(11):1050-61 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16221805.
  7. Corley DA, Kubo A, Levin TR, Block G, Habel L, Rumore G, et al. Race, ethnicity, sex and temporal differences in Barrett's oesophagus diagnosis: a large community-based study, 1994-2006. Gut 2009 Feb;58(2):182-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18978173.
  8. 8.0 8.1 Edelstein ZR, Bronner MP, Rosen SN, Vaughan TL. Risk factors for Barrett's esophagus among patients with gastroesophageal reflux disease: a community clinic-based case-control study. Am J Gastroenterol 2009 Apr;104(4):834-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19319131.
  9. Corley DA, Kubo A, Levin TR, Block G, Habel L, Zhao W, et al. Helicobacter pylori infection and the risk of Barrett's oesophagus: a community-based study. Gut 2008 Jun;57(6):727-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17895354.
  10. Thrift AP, Pandeya N, Smith KJ, Green AC, Hayward NK, Webb PM, et al. Helicobacter pylori infection and the risks of Barrett's oesophagus: a population-based case-control study. Int J Cancer 2012 May 15;130(10):2407-16 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21681741.
  11. Anderson LA, Cantwell MM, Watson RG, Johnston BT, Murphy SJ, Ferguson HR, et al. The association between alcohol and reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Gastroenterology 2009 Mar;136(3):799-805 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19162028.
  12. Kubo A, Levin TR, Block G, Rumore GJ, Quesenberry CP Jr, Buffler P, et al. Alcohol types and sociodemographic characteristics as risk factors for Barrett's esophagus. Gastroenterology 2009 Mar;136(3):806-15 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19111726.
  13. Thrift AP, Pandeya N, Smith KJ, Mallitt KA, Green AC, Webb PM, et al. Lifetime alcohol consumption and risk of Barrett's Esophagus. Am J Gastroenterol 2011 Jul;106(7):1220-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21427711.
  14. Steevens J, Schouten LJ, Driessen AL, Huysentruyt CJ, Keulemans YC, Goldbohm RA, et al. A prospective cohort study on overweight, smoking, alcohol consumption, and risk of Barrett's esophagus. Cancer Epidemiol Biomarkers Prev 2011 Feb;20(2):345-58 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21173169.
  15. Anderson LA, Johnston BT, Watson RG, Murphy SJ, Ferguson HR, Comber H, et al. Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence. Cancer Res 2006 May 1;66(9):4975-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16651456.
  16. Thrift AP, Pandeya N, Smith KJ, Green AC, Webb PM, Whiteman DC. The use of nonsteroidal anti-inflammatory drugs and the risk of Barrett's oesophagus. Aliment Pharmacol Ther 2011 Nov;34(10):1235-44 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21967506.
  17. Kendall BJ, Macdonald GA, Hayward NK, Prins JB, Brown I, Walker N, et al. Leptin and the risk of Barrett's oesophagus. Gut 2008 Apr;57(4):448-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18178609.
  18. Thompson OM, Beresford SA, Kirk EA, Bronner MP, Vaughan TL. Serum leptin and adiponectin levels and risk of Barrett's esophagus and intestinal metaplasia of the gastroesophageal junction. Obesity (Silver Spring) 2010 Nov;18(11):2204-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20111023.
  19. Andrici J, Tio M, Cox MR, Eslick GD. Hiatal Hernia and the Risk of Barrett's Esophagus: A Meta-Analysis. J Gastroenterol Hepatol 2012 Jun 13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22694245.
  20. 20.0 20.1 Chak A, Lee T, Kinnard MF, Brock W, Faulx A, Willis J, et al. Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 2002 Sep;51(3):323-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12171951.
  21. Thrift AP, Kendall BJ, Pandeya N, Vaughan TL, Whiteman DC, Study of Digestive Health. A clinical risk prediction model for Barrett esophagus. Cancer Prev Res (Phila) 2012 Sep;5(9):1115-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22787114.
  22. Cummings LC, Shah N, Maimone S, Salah W, Khiani V, Chak A. Barrett's esophagus and the risk of obstructive sleep apnea: a case-control study. BMC Gastroenterol 2013 May 11;13:82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23663216.
  23. Leggett CL, Gorospe EC, Calvin AD, Harmsen WS, Zinsmeister AR, Caples S, et al. Obstructive Sleep Apnea is a Risk Factor for Barrett's Esophagus. Clin Gastroenterol Hepatol 2013 Sep 11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24035775.

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Appendices


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