Hirschsprung disease as a panenteric disorder: Systematic review of histological and molecular alterations in the ganglionic segment
DOI:
https://doi.org/10.5281/zenodo.18216152Keywords:
Hirschsprung disease, enteric nervous system, interstitial cells of Cajal, intestinal neuronal dysplasia, enterocolitis, systematic reviewAbstract
Introduction: Hirschsprung disease (HD) is traditionally defined by distal aganglionosis. However, the persistence of dysmotility, constipation and enterocolitis (HAEC) after a technically successful surgery suggests that the pathology extends beyond the resected segment. This study evaluates the hypothesis of HD as a “panenteric disorder,” analyzing alterations in the proximal ganglionic segment considered histologically normal.
Methods: A systematic review was conducted following PRISMA guidelines in the PubMed, LILACS and Scopus databases, with no date restriction. Studies analyzing histological, molecular, neurochemical or immunological alterations in the proximal ganglionic intestine of patients with confirmed HD were included. Methodological quality was assessed using JBI tools.
Results: The synthesized evidence shows that the proximal ganglionic segment is not functionally normal. Four key pathological patterns were identified: (1) Structural alterations in support networks, including reduced density of interstitial cells of Cajal (ICC) and aberrant dendritic morphology in enteric glia; (2) Neurochemical dysregulation, characterized by overexpression of nitric oxide synthase (nNOS) and irregular organization of cholinergic fibers; (3) High prevalence of intestinal neuronal dysplasia type B (IND-B) and neuronal immaturity (PSA-NCAM markers) in the anastomotic zone; and (4) Mucosal barrier dysfunction with defective mucin and IgA production, predisposing to chronic inflammation.
Conclusion: HD is not an isolated segmental pathology but a generalized disorder of the enteric nervous system. “Invisible” abnormalities in the ganglionic segment (ICC deficiency, glial and neurochemical dysfunction) are critical determinants of postoperative morbidity. Reassessment of intraoperative biopsy protocols is suggested to include markers of neuronal quality rather than ganglionic presence alone.
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Copyright (c) 2026 Iago Rocha Caetano, Poliana Raquel Viana Cordeiro Nascimento, Gabriel da Silva Soares, Vinícius Ferreira Gomes, Melanie Rosenscheg Pacheco , Theresa Cristina Cavalcante Cândido Silva , Jordana Vitória Da Silva Freitas, Marcella Martins Fernandes, Jamylle Oliveira Freitas, Nathália Dourado da Paixão, Andrea Paola Britos Gómez (Autor/a)
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