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What factors suggest a genetic origin for this disorder?
5.J. Sontag (Hines, Illinois)
More than 40 years since Barrett made the original observation of the disease named after him, the etiology of Barrett's esophagus remains an enigma. Based on 22 years of experience, Borrie and Goldwater [1] proposed that Barrett's esophagus in children was congenital and in adults was acquired. They suggested a bimodal distribution consisting of a 0 to 10-year-old group and a group 40 years and older. Unfortunately, the investigators had no patients under the age of 11 to support their proposal.
A number of reports suggest that Barrett's esophagus may be genetic in origin. Gelfand reported Barrett's esophagus in identical female twins in their sixties [2]. Grabb reported Barrett's esophagus in an 80-year-old male, his son and his two daughters [3]. Everhart reported a 40-year-old male and his two teenage sons, all of whom had Barrett's esophagus [4]. Jochem reported Barrett's esophagus in six males over 3 generations in one family [5]. The distribution of Barrett's epithelium in these cases suggests a genetic autosomal dominant inheritance. It has been suggested by several authors that the gastroesophageal (GE) reflux, not the Barrett's epithelium, is the condition that is inherited [6,7].
The belief that gastric columnar epithelium in the tubular esophagus has a congenital (existing at birth) component has been difficult to support. Up until 17 weeks of gestation, the embryological esophagus is lined with ciliated columnar epithelium. At about this time, a small focus of squamous epithelium, which appears in the columnar epithelium at the level of the midesophagus, begins to migrate proximally and distally [8]. By 40 weeks gestation, the original columnar lined esophagus should be completely replaced by squamous epithelium. If Barrett's epithelium were truly congenital, one would expect to find newborn infants and very young children with specialized columnar or gastric epithelium in the distal esophagus. Such findings have not been reported in autopsy studies of neonates [9]. In addition, Barrett's esophagus with specialized columnar epithelium occurs rarely in young children. In six studies of children with Barrett's esophagus, comprising more than 1500 children, specialized columnar epithelium was documented in only 34 - the youngest of which was 5 years old [10-15].
It is likely, therefore, that Barrett's epithelium results from congenital GE reflux. We propose the following sequence of events to explain the development of squamous esophagitis in some individuals and Barrett's epithelium in others and the finding of gastric epithelium in younger children and specialized columnar epithelium in adults. Our hypothesis is as follows: 1) an incompetent antireflux barrier at the GE junction is a congenital condition that occurs as a result of incomplete development due to premature birth; 2) subsequent acid reflux may cause either squamous esophagitis or the development of Barrett's epithelium, depending on how much squamous epithelial replacement of the embryonic columnar epithelium had occurred in utero. If squamous epithelium had not completely replaced the columnar epithelium, then an incomplete squamocolumnar junction will be present along with the congenital GE reflux. In such a case, biopsy of the distal esophagus in the area of columnar epithelium during early childhood may reveal gastric-type of epithelium; 3) as reflux worsens, however, and bile becomes a component of the acid reflux, the pleuripotential cell may differentiate into specialized columnar epithelium. On the other hand, if the squamocolumnar junction has been completed at birth, despite the presence of congenitally-acquired GE reflux, squamous esophagitis will be the result of the chronic acid injury. Such a scenario might explain why junctional and fundic epithelium are found so frequently in younger patients with reflux, whereas specialized columnar epithelium is reserved for older children and adults. It is possible that the change from gastric epithelium to specialized epithelium requires years of reflux in addition to the presence of bile in the refluxate. It is not known
why some patients with Barrett's esophagus go on to develop adenocarcinoma while the vast majority do not.
Prevalence of Barrett's in children
A number of authors have attempted to define the prevalence of Barrett's esophagus in the pediatric population [10-15]. Unfortunately, these studies give little insight into the true prevalence of Barrett's esophagus in children. For example, most of the studies were retrospective, the sites of biopsies often were haphazard and not planned and most of the biopsies were taken at least 2 cm proximal to the visual GE junction, which would easily miss all the children with short segment Barrett's. Furthermore, the method used to report the prevalence of Barrett's was incorrect: the ratio of specialized columnar epithelium patients to total columnar epithelium patients was used to report the prevalence of Barrett's, rather than the ratio of specialized columnar patients to the total pediatric population undergoing endoscopy. Thus the prevalence of specialized columnar, which ranges from less than 1.0 to 5%, is based on a total of only 34 children with specialized columnar epithelium. The true number of patients with Barrett's may have been overestimated (due to the use of an inappropriately low total number of patients at risk) or underestimated (due to sampling errors immediately above the gastroesophageal junction). These studies, however, do suggest that specialized columnar epithelium in children is rare.
In conclusion, genetic factors may possibly be involved in some cases of Barrett's esophagus, probably as an autosomal dominant factor, but genetic factors as a major cause of Barrett's cannot be supported or refuted based on the available data. Most of the available data suggest that GE reflux is congenital. Finally, the apparently lower prevalence of Barrett's in children and higher prevalence in adults suggest that Barrett's esophagus is acquired as a result of the congenital GE reflux.
References
8. Johns BAE. Developmental changes in the oesophageal epithelium in man. J Anat 1952;86:431-439.