Associations of Mucosal Nerve Fiber Innervation Density with Hirschsprung-Associated Enterocolitis: A Retrospective Three-Center Cohort Study

Abstract

Hirschsprung disease (HSCR) is a congenital intestinal neurodevelopmental disorder characterized by the absence of enteric ganglion cells in the distal colon. Although Hirschsprung-associated enterocolitis (HAEC) is the most frequent life-threatening complication in HSCR, to date reliable biomarkers predicting the likelihood of HAEC are yet to be established. We established a three-center retrospective study including 104 HSCR patients surgically treated between 1998–2019. Patient-derived cryo- or paraffin-preserved colonic tissue at surgery was analyzed via beta III tubulin immunohistochemistry. We subsequently determined extrinsic mucosal nerve fiber density in resected rectosigmoid specimens and classified HSCR patients accordingly into nerve fiber-high or fiber-low groups. We compared the distribution of clinical parameters obtained from medical records between the fiber-high (n=36) and fiber-low (n=68) patient groups. We assessed the association between fiber phenotype and enterocolitis using univariate and multivariate logistic regression adjusted for age at operation. Enterocolitis was more prevalent in patients with sparse mucosal nerve fiber innervation (fiber-low phenotype, 87%) compared to the fiber-high phenotype (13%; p=0.002). In addition, patients developing enterocolitis had a younger age at surgery (3 months versus 7 months; p=0.016). In the univariate analysis, the odds for enterocolitis development in the fiber-low phenotype was 5.26 (95% CI 1.67–16.59; p=0.005) and 4.01 (95% CI 1.22–13.17; p=0.022) when adjusted for age. Here we showed that HSCR patients with a low mucosal nerve fiber innervation grade in the distal aganglionic colon have a higher risk of developing HAEC. Consequently, histopathologic analysis of the nerve fiber innervation grade could serve as a novel sensitive prognostic marker associated with the development of enterocolitis in HSCR patients.

Hirschsprung's disease associated enterocolitis: A comprehensive review

“…These findings were later corroborated in a human study and most importantly, demonstrated a possible correlation with clinical outcomes[ 32 ]. In contrary, a retrospective study in humans concluded that in HSCR patients with a low mucosal nerve fiber innervation grade in the distal aganglionic bowel have a higher risk of developing HAEC[ 33 ]. Similarly, a prospective study also demonstrated that lack of cholinergic innervation in the distal colon of HSCR patients was associated with increased risk of postoperative HAEC[ 34 ].…”

Intervention effects and related mechanisms of glycyrrhizic acid on zebrafish with Hirschsprung-associated enterocolitis

“…However, in recent years, it was reported in studies that up to 40% of children with HD still develop HAEC after definitive operation for Hirsch-sprung disease. Histopathological studies have shown that HAEC can occur in areas of the intestine with both ganglion and non-ganglion cells, and that there are persistent inflammatory lesions in the intestine after enterostomy, indicating that the lack of ganglion cells is not the only cause of HAEC[ 7 - 9 ]. Current theories suggest that the factors causing HAEC mainly include intestinal mechanical obstruction, intestinal infection, intestinal mucosal barrier damage, increased activity of prostaglandin E1, changes in mucin composition, and past medical history of HAEC.…”