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Does Barrett's mucosa develop in children not suffering from reflux?
E. Hassall (Vancouver)
In 1976, Borrie and Goldwater proposed a congenital etiology for BE in children and an acquired etiology in adults [1], based on their finding of a bimodal distribution of patients - a group 0-10 years and a group over 40 years of age. However, their youngest patient with columnar mucosa (of unspecified nature) on biopsy was 11 years old, therefore the accuracy of diagnosis and conclusions regarding their under 10-year-olds is questionable.
Since that proposal, other evidence has been cited in support of a congenital etiology. One newborn in an autopsy study [2] was found to have an esophagus "completely lined with columnar epithelium except for two tiny patches of squamous epithelium", however, the type of columnar epithelium was not specified, as in a previous study [3], it was likely ciliated columnar epithelium which had not yet desquamated. There is no evidence it was Barrett's specialized epithelium. Further evidence against a purely congenital etiology is that BE has not been found in any autopsy study of neonates [2-4]. The occurrence of BE in very young children could suggest a congenital cause, however, claims of BE occurring in children under 5 years of age [5-7] are not supported by adequate documentation [8], all cases have been single biopsy diagnoses without specialized epithelium. The mere occurrence of BE in children [5,6,9,10] is not supportive of a purely congenital cause, as in all well-documented childhood cases of BE, chronic severe GE reflux has been present. Similarly, the presence per se of a total columnar-lined esophagus in an adult [11] is not supportive as the patient had a hiatal hernia and longstanding reflux. An interesting report [12] was that of a 14-month-old child with a bleeding, penetrating giant ulcer in the distal esophagus. The ulcer had gastric mucosa at the margins and was surrounded by squamous mucosa. The authors concluded that this was a congenital Barrett's ulcer but specialized mucosa was not present. Rather, it may represent congenital gastric heterotopia of the esophagus, with an unusual course
analogous to Meckels diverticulum. Thus, most of the evidence for a purely congenital etiology can be refuted.
That genetic factors may play a role is illustrated by the occurrence of BE in several families [13]. However, GE reflux was present in all cases. Due to these cases, an autosomal dominant inheritance has been proposed, however, it is unclear whether it is Barrett's epithelium or GE reflux that might be inherited [14,15]. In any case, the overwhelming number of patients with BE has no family history of such, therefore it is necessary to consider etiologies other than purely genetic for the majority of cases.
In contrast there is voluminous and compelling evidence to implicate GE reflux as the usual inciting and ongoing injurious factor in the pathogenesis of BE [13,16]. A severe injury and an abnormal chemical environment (continued exposure to refluxate) during repair, might result in BE. That BE is a purely congenital disorder in some patients is unsupported by any evidence, but a congenital component cannot be entirely ruled out. This factor might explain the development of BE in only some persons with reflux.
This question also raises the issue of the development of BE due to other injuries (e.g., following mucositis due to chemotherapy). Barrett's esophagus has been described at autopsy in three children who had received chemotherapy for leukemia [17]. One child had the lower one-third of esophagus occupied by fundic gland mucosa, another had 4 cm of fundic gland mucosa distally, and the third child had 4 cm of mixed fundic and cardiac gland mucosa. In another study of 16 women who underwent chemotherapy for breast cancer [18], nine had the Z-line displaced 4-9 cm proximally, but columnar mucosa was present in biopsies > 4 cm in only six patients. Of these six patients only three had "intestinal type" mucosa, which was not further described.
While the children [17] might not meet current criteria for BE and only three of the adults may have developed BE [18], the concept that some form of columnar metaplasia may develop after chemotherapy is intriguing. It does fit with one hypothesis of pathogenesis of BE, that is, severe mucosal injury (in this case, mucositis) healing abnormally in an injurious milieu, i.e., acid or alkaline reflux. While reflux was not documented in these studies [17,18], it is recognized that cancer patients undergoing chemotherapy often have delayed gastric emptying, nausea, vomiting and esophagitis, i.e., some of these patients may have de novo or transient pathologic reflux due to their cancer or cancer therapy.
However, the implication of these studies that BE often follows cytotoxic therapy, has been challenged by a recent report in which none of 15 women receiving chemotherapy for breast cancer developed BE [19]. In Sartori's study [18], endoscopy had been performed before chemotherapy and 1 month after the completion of 6 months of chemotherapy. In a more recent report [19], follow-up endoscopy was done at a mean of 31 months after completion of chemotherapy. It is possible that columnar metaplasia developed during treatment, then regressed in the 2.5 years after treatment ended.
One may conclude that, at present, there is little evidence to support a solely nonreflux etiology of BE in children.
References
13. Hassall E. Barrett's esophagus: congenital or acquired? Am J Gastroenterol 1993;88:8l9-824.