Acquired Esophageal Strictures in Children: Morphometric and Immunohistochemical Analyses.

BACKGROUND: Esophageal strictures (ES) in children are not well characterized pathologically. We report unique histopathologic analyses of resected acquired ES and control esophagi (CE). METHODS: Muscle layer thicknesses were measured in intact well-oriented areas; inflammatory cells were counted in the most inflamed high power field (hpf). Sections were stained with relevant antibodies. Results were expressed as median, lower and upper quartiles. Wilcoxon Rank Sums non-parametric test was used to compare groups; P ≤ 0.05 was considered significant. RESULTS: All ES (N = 10) showed focal replacement of lamina propria, muscularis mucosa and submucosa by actin+ fibers emanating from muscularis propria. Compared to CE (N = 8), ES displayed significantly thickened muscularis mucosa and propria, and increased mast cells (tryptase- and chymase-positive), and eosinophils in muscle layers (all P ≤ 0.01). Matrix proteins periostin and fibronectin were identified in the muscle layers of CE, and in the extracellular matrix in areas of disrupted architecture in ES. CONCLUSIONS: Compared to CE, acquired ES in children show significant structural alterations, including obliterative muscularization, inflammatory cell mural infiltrates, and extracellular matrix protein deposits. Therapies targeting connective tissue expansion, mast cells, eosinophils and inflammation may be beneficial to treat ES.

Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown. OBJECTIVE: To quantify the risk associated with genes and environment on familial clustering of EoE. METHODS: Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined. RESULTS: Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% (P < .001), and common family environment contributed 81.0% ± 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status. CONCLUSIONS: EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).

Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.

BACKGROUND & AIMS: Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. METHODS: We developed an EoE diagnostic panel (EDP) comprising a 96-gene quantitative polymerase chain reaction array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14) and subsequently vetted the EDP using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed, paraffin-embedded tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. RESULTS: The EDP identified adult and pediatric patients with EoE with approximately 96% sensitivity and approximately 98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with formalin-fixed, paraffin-embedded tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse after treatment. CONCLUSIONS: We developed a molecular diagnostic test (referred to as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.