Fibrosis IBD

Roger Feakins, H-ECCO Member

Roger Feakins

Fibrosis and other connective tissue abnormalities are common in IBD, especially in Crohn’s Disease. The main clinical consequence is strictures, occurring most often in the small bowel or at the ileocaecal/ileocolic junction. Surgery may be necessary for stricture management.

Fibrosis-predominant strictures are less responsive than inflammation-predominant strictures to medical therapy. However, there is overlap between these types. Also, smooth muscle abnormalities and other connective tissue changes are important. Possibly, there is a “chronic inflammation–fibrosis–smooth muscle hyperplasia” sequence [1–4].

Fibrosis is probably a consequence of extracellular matrix deposition in excessive amounts. Cells responsible may include fibroblasts, myofibroblasts and smooth muscle cells (i.e. mesenchymal cells) and cells derived from a process of epithelial–mesenchymal transition. Other factors include abnormalities of matrix metalloproteinases, collagens, tenascin, tumour necrosis factor alpha and transforming growth factor beta. Derangement of intestinal flora, genetic abnormalities, DNA methylation and miRNAs may also contribute [5–9]. Fat wrapping, a feature typical of Crohn’s Disease, correlates with fibrosis, muscular changes and stricturing. Therefore, adipocyte cytokines could play a role in the process [2, 4, 10, 11]. Blood vessel degeneration, inflammation and proliferation may also occur in Crohn’s Disease, raising the possibility that ischaemia is a factor [1, 2]. Identification of suitable targets for anti-fibrotic drugs offers the possibility of future improvements in therapy [9].

Definitions of a stricture usually require narrowing of the lumen and variably include other items such as pre-stenotic dilatation and thickening of the wall. Histologically, connective tissue changes often affect all layers and include fibrosis, neural hyperplasia and vascular proliferation [2, 12–14]. The muscle layers can undergo demonstrate hypertrophy, hyperplasia, disorganisation and duplication. Muscle fibres may extend into other layers, particularly the submucosa, accompanied by vascular changes and leading to “obliterative muscularisation of the submucosa” [1].

Precise documentation of pathological changes in Crohn’s Disease strictures may be part of the assessment of the efficacy of new anti-stricture drugs and can be a reliable way to categorise response to therapy, also allowing comparison with imaging findings. Attempts to standardise scoring and to produce a scheme that is suitable for clinical trials are in progress [3, 15–18].

Clinically, there is a differential diagnosis for strictures in Crohn’s Disease that includes tumour, drugs, chronic ischaemia, chronic infection and diverticulosis. This is important because the possibility of neoplasia always requires consideration, especially when a stricture is persistent and difficult to manage.


  1. Shepherd NA, Jass JR. Neuromuscular and vascular hamartoma of the small intestine: is it Crohn's disease? Gut 1987;28:1663–8.
  2. Shelley-Fraser G, Borley NR, Warren BF, Shepherd NA. The connective tissue changes of Crohn’s disease. Histopathology 2012;60:1034–44.
  3. De Voogd FA, Mookhoek A, Gecse KB, et al. Systematic review: Histological scoring of strictures in Crohn’s disease. J Crohns Colitis 2020;14:734–42.
  4. Chen W, Lu C, Hirota C, et al. Smooth muscle hyperplasia/hypertrophy is the most prominent histological change in Crohn's fibrostenosing bowel strictures: A semiquantitative analysis by using a novel histological grading scheme. J Crohns Colitis 2017;11:92–104.
  5. Zorzi F, Calabrese E, Monteleone G. Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease. Clin Sci (Lond) 2015;129:1107–13.
  6. Mehta SJ, Lewis A, Nijhuis A, et al. Epithelial down-regulation of the miR-200 family in fibrostenosing Crohn's disease is associated with features of epithelial to mesenchymal transition. J Cell Mol Med 2018;22:5617–28.
  7. Lewis A, Nijhuis A, Mehta S, et al., Intestinal fibrosis in Crohn's disease: role of microRNAs as fibrogenic modulators, serum biomarkers, and therapeutic targets. Inflamm Bowel Dis 2015;21:1141–50.
  8. Rodriguez-Lago I, Gisbert JP. The role of immunomodulators and biologics in the medical management of stricturing Crohn's disease. J Crohns Colitis 2020;14:557–66.
  9. Lewis A, Sánchez S, Berti G, et al. Small-molecule Wnt inhibitors are a potential novel therapy for intestinal fibrosis in Crohns disease. Clin Sci (Lond) 2022;136:1405–23.
  10. Li Y, Ge Y, Gong J, et al. Mesenteric lymphatic vessel density is associated with disease behavior and postoperative recurrence in Crohn's disease. J Gastrointest Surg 2018;22:2125–32.
  11. Mao R, Kurada S, Gordon IO, et al. The mesenteric fat and intestinal muscle interface: Creeping fat influencing stricture formation in Crohn's disease. Inflamm Bowel Dis 2019;25:421–26.
  12. Gordon IO, Bettenworth D, Bokemeyer A, et al. Histopathology scoring systems of stenosis associated with small bowel Crohn's disease: A systematic review. Gastroenterology 2020;158:137–50 e1.
  13. Borley NR, Mortensen NJ, Jewell DP, Warren BF. The relationship between inflammatory and serosal connective tissue changes in ileal Crohn's disease: evidence for a possible causative link. J Pathol 2000;190:196–202.
  14. Borley NR, Mortensen NJ, Kettlewell MG, George BD, Jewell DP, Warren BF. Connective tissue changes in ileal Crohn's disease: relationship to disease phenotype and ulcer-associated cell lineage. Dis Colon Rectum 2001;44:388–96.
  15. Wagner M, Mabel Ko H, Chatterji M, et al. Magnetic resonance imaging predicts histopathological composition of ileal Crohn's disease. J Crohns Colitis 2018;12:718–29.
  16. de Sousa HT, Estevinho MM, Peyrin-Biroulet L, et al. Transmural histological scoring systems in Crohn's disease: a systematic review with assessment of methodological quality and operating properties. J Crohns Colitis 2020;14:743–56.
  17. Gordon IO, Bettenworth D, Bokemeyer A, et al. International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease. Gut 2022;71:479–86.
  18. Feakins RM. Transmural histology scores in stricturing Crohn's disease: Seeking to build precision on uncertain foundations. J Crohns Colitis 2020;14:721–3.

Posted in ECCO News, Committee News, Volume 18, Issue 4, H-ECCO