Primary Motility  Disorders of the  Esophagus
 The Esophageal
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 Barrett's
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OESO©2015
 
Volume: Barrett's Esophagus
Chapter: Etiology and origins of Barrett's epithelium
 

Can a familial prevalence of Barrett's esophagus be demonstrated?

A.J. Cameron (Rochester)

Research supported by a grant from the American Digestive Health Foundation and by a General Clinical Research Center grant from the National Institutes of Health (M01 RR00585.)

There are multiple families reported in the literature in whom 2 or more members have Barrett's esophagus. In some reports other family members had adenocarcinoma of the esophagus. Also, in some reports, gastroesophageal reflux disease (GERD) without Barrett's esophagus was found in other family members.

Barrett's esophagus was reported in a father and 2 sons [1], in two sisters [2] and in a pair of identical twins [3]. Crabb et al. [4] reported a large family in whom 4 relatives had Barrett's esophagus, 2 with adenocarcinoma of the esophagus. Jochem et al. [5] described a family with 6 relatives in 3 generations having Barrett's esophagus, 3 with adenocarcinoma of the esophagus. Fahmy and King [6] reported 4 families with 2 or 3 cases of Barrett's esophagus in each, and adenocarcinoma of the esophagus in 2 of these families. Eng et al. [7] found Barrett's esophagus in 7 members of one family, 2 with adenocarcinoma of the esophagus. Poynton et al. [8] reported two sib pairs and one father and daughter with adenocarcinoma of the esophagus in Barrett's esophagus. Carre et al. [9] described a family with hiatal hernia (HH) in 23 of 38 relatives; a mother and daughter had Barrett's esophagus, and the grandmother died of adenocarcinoma of the esophagus. An autosomal dominant liability to develop reflux [4], to develop HH [9] or to develop Barrett's esophagus [5] in these families was proposed. Investigation of relatives of Barrett's esophagus patients who had reflux symptoms was recommended [1, 5].

These reports showed that in certain families there was a familial, likely genetic, clustering of Barrett's esophagus and adenocarcinoma of the esophagus. Other possibilities that seem less likely are an environmental factor operating in early life; or familial clustering occurring by chance, with publication bias to report such unusual families. Romero et al. therefore decided to do a prospective statistical investigation of the families of consecutively seen patients with reflux diseases, and this was published in 1997 [10].

In our first study [10], we investigated the prevalence of reflux symptoms in the first degree relatives (living parents, siblings and adult children] of 40 patients with Barrett's esophagus, 27 with adenocarcinoma of the esophagus, and 55 with uncomplicated reflux esophagitis. The spouses of these patients and the spouse's first degree relatives acted as controls. Information was obtained from a total of 940 individuals, who completed a reflux symptom questionnaire based on a previously validated measure. Logistic regression was used to adjust for the effects of age, gender, obesity and smoking. We showed that reflux symptoms (heartburn or acid regurgitation) were significantly more common in the parents and siblings of patients with Barrett's esophagus (46% versus 27%) or adenocarcinoma of the esophagus (43% versus 23%), compared to controls. The adjusted odds ratios were 2.2 for Barrett's esophagus relatives and 2.8 for relatives of patients with adenocarcinoma of the esophagus. When we compared the spouses of patients with Barrett's esophagus with the same-sex siblings of patients with Barrett's esophagus, the siblings (shared genes) also had a higher prevalence of reflux symptoms than the (shared environment) spouses, 41% versus 12%, odds ratio 9.8. In our study, we showed a small and non-significantly greater prevalence of symptoms in relatives of patients with reflux esophagitis.

A somewhat similar study was reported by Trudgill et al. in 1999 [11]. The first degree relatives of 30 patients in each of several reflux diagnostic categories completed a reflux symptom questionnaire. Relatives of age and sex matched patients without reflux symptoms acted as controls. Information was obtained from a total of 418 relatives. Logistic regression was used to adjust for the effects of potential confounding factors. For Barrett's esophagus, there was a significantly increased probability that first degree relatives would have reflux symptoms occurring at least weekly, the odds ratio being 4.8 (95 % CI, 1.7-13.4). Relatives of patients with reflux disease but no Barrett's esophagus were found to have an increased risk for reflux symptoms. For example, the odds ratio for weekly reflux symptoms in relatives of patients with both increased acid reflux on pH monitoring and low pressure in the lower esophageal sphincter, was 3.9 (95% CI, 1.3-11.5).

Comparison between the studies of Trudgill et al. and ours shows that both reports found an increased prevalence of reflux symptoms in relatives of patients with Barrett's esophagus. However, one study showed an increased prevalence of reflux in relatives of patients with uncomplicated reflux disease and one did not show a significant increase.

It seems clear that genetic influences play a part in the development of reflux or Barrett's esophagus. In the 2 studies above, relatives were only investigated by a symptom questionnaire. In our latest study, we proceeded with objective testing of relatives [12]. The aim of our study was to find if Barrett's esophagus relatives with reflux symptoms are more liable to have Barrett's esophagus than unrelated persons with similar reflux symptoms. We found 140 index patients with Barrett's esophagus who were willing to provide us with the names and addresses of their first degree relatives. Out of 682 relatives, 427 (63%) responded to our request to complete a reflux symptom questionnaire. Sixty two of the 427 had a previous endoscopy elsewhere, and we were able to review the records and pathologic slides of 41 of these. Nine of the 41 had a Barrett's esophagus. Our main focus was on the relatives with heartburn or acid reflux occurring at least once per week or more, and who had not been previously investigated. One hundred and thirty eight of 365 (38%) relatives with no previous endoscopy met our criteria for weekly reflux symptoms. We prospectively performed endoscopy on the first available 100 of these symptomatic first degree relatives of patients with Barrett's esophagus. As a control group, we simultaneously did endoscopy on 100 patients with similar frequency of reflux symptoms, who had no known relative with Barrett's esophagus and no previous endoscopy. These groups are compared in Table I.

Table I. Comparison of relative and symptomatic control groups.

The relative and control groups were fairly well matched. The relatives were somewhat younger than the controls which might result in a slightly lower risk for Barrett's esophagus; but the relatives also had a longer mean duration of reflux symptoms, which might increase their risk for Barrett's esophagus. These differences between the 2 subject groups would tend to cancel each other.

Reflux esophagitis was found in 71 relatives and in 58 controls.

The prevalence of Barrett's esophagus in the 2 groups is compared in Table II.

Table II. Prevalence of Barrett's esophagus in relatives compared to controls.

The most important finding was that Barrett's esophagus (long segment, 3 cm or more with intestinal metaplasia) occurred in 8% of relatives with reflux symptoms versus 5% of controls with similar reflux symptoms. This was not a significant difference.

We interpret the results as showing that a person with reflux symptoms and one first degree relative with Barrett's esophagus is not at greater risk of developing Barrett's esophagus than other persons with reflux symptoms and no family history of Barrett's esophagus. Male sex, increased age, and a long history of reflux symptoms were stronger predictors of Barrett's esophagus than having a family member with that diagnosis.

We included 200 patients with no previous endoscopy in the study, and found a total of 13 new cases of Barrett's esophagus. A larger series might or might not show a significant increase in Barrett's esophagus in the symptomatic relatives. We did not study the asymptomatic relatives, thinking that they would have a low risk for Barrett's esophagus or esophagitis.

The results need to be interpreted with caution. The reported family pedigrees discussed in the introduction, with multiple cases in the same kindred, are impressive. Until more data can be accumulated, it appears that a few families have a genetic predisposition to reflux disease and Barrett's esophagus, but that in most instances, Barrett's esophagus is sporadic.

In the 2 previous papers [10, 11] it had been shown that relatives of Barrett's esophagus patients had an increased prevalence of reflux symptoms, with odds ratios of 2.2-4.8. The endoscopic results reported above showed that reflux esophagitis was at least as common in symptomatic relatives as in symptomatic non-relatives. This provides objective confirmation that reflux disease, not just symptoms, is familial in Barrett's esophagus.

In summary, it appears that reflux disease shows familial clustering. Barrett's esophagus may occur in families with an increased prevalence of reflux disease, but Barrett's esophagus itself only shows familial clustering in a few families.

References

1. EverhartCW Jr , Holzapple PG, Humphries TJ. Occurrence of Barrett's esophagus in three members of the same family: first report of familial incidence. Gastroenterology 1978;74:A1032.

2. Prior A, Whorwell PJ. Familial Barrett's esophagus? Hepatogastroenterology 1986;33:86-87.

3. Gelfand MD. Barrett esophagus in sexagenarian identical twins. J Clin Gastroenterol 1983;5:251-253.

4. Crabb DW, Berk MA, Hall TR, Conneally PM, Biegel AA, Lehman GA. Familial gastroesophageal reflux and development of Barrett's esophagus. Ann Int Med 1985;103:52-54.

5. Jochem VJ, Fuerst PA, Fromkes JJ. Familial Barrett's esophagus associated with adenocarcinoma. Gastroenterology 1992;102:1400-1402.

6. Fahmy N, King JF. Barrett's esophagus: an acquired condition with genetic predisposition. Am J Gastroenterol 1993;88:1262-1265.

7. Eng C, Spechler SJ, Ruben R, Li FP. Familial Barrett's esophagus and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 1993;2:397-399.

8. Poynton AR, Walsh TN, O'Sullivan G, Hennessy TPJ. Carcinoma arising in familial Barrett's esophagus. Am J Gastroenterol 1996;91:1855-1856.

9. Carre IJ, Johnston BT, Thomas BS, Morrison PJ. Familial hiatal hernia in a large five generation family confirming true autosomal dominant inheritance. Gut 1999;45:649-642.

10. Romero Y, Cameron AJ, Locke III GR, Schaid DJ, Slezak JM, Branch CD, Melton III LJ. Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology 1997;113:1449-1456.

11. Trudgill NJ, Kapur KC, Riley SA. Familial clustering of reflux symptoms. Am J Gastroenterol 1999;94:1172-1178.

12. Romero Y, Cameron AJ, Hardtke CL, Locke GR III, McDonnell SK, Murray JA, Burgart LJ, Azodo I, Schaid DJ. Barrett's esophagus, a familial disorder? Gastroenterology 2000;118:A222.


Publication date: August 2003 OESO©2015