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.

先天性巨结肠症 (HSCR) 是一种先天性肠道神经发育障碍，其特征是远端结肠缺乏肠神经节细胞。尽管先天性巨结肠相关小肠结肠炎 (HAEC) 是 HSCR 中最常见的危及生命的并发症，但迄今为止，尚未建立预测 HAEC 可能性的可靠生物标志物。我们建立了一项三中心回顾性研究，纳入 1998 年至 2019 年间接受手术治疗的 104 名 HSCR 患者。通过 β III 微管蛋白免疫组织化学分析手术时患者来源的冷冻或石蜡保存的结肠组织。随后，我们测定了切除的直肠乙状结肠标本中的外在粘膜神经纤维密度，并将 HSCR 患者相应地分为神经纤维高组或纤维低组。我们比较了从医疗记录中获得的临床参数在高纤维 (n=36) 和低纤维 (n=68) 患者组之间的分布。我们使用根据手术年龄调整的单变量和多变量逻辑回归评估纤维表型与小肠结肠炎之间的关联。与纤维高表型（13%；p=0.002）相比，小肠结肠炎在粘膜神经纤维分布稀疏的患者（纤维低表型，87%）中更为常见。此外，发生小肠结肠炎的患者手术年龄较小（3 个月与 7 个月；p=0.016）。在单变量分析中，根据年龄进行调整后，低纤维表型中发生小肠结肠炎的几率为 5.26（95% CI 1.67-16.59；p=0.005）和 4.01（95% CI 1.22-13.17；p=0.022）。在这里，我们发现远端无神经节结肠粘膜神经纤维神经支配等级较低的 HSCR 患者发生 HAEC 的风险较高。因此，神经纤维神经支配等级的组织病理学分析可以作为与 HSCR 患者小肠结肠炎发生相关的新型敏感预后标志物。