Intestinal Lymphedema and Structural Changes in Crohn's Disease Pathologic process of Crohn’s disease

Main Article Content

Pietro Tonelli


Background and Aims: In 1954 Warren and Sommers asserted that Crohn’s disease was “essentially an elephantiasis of the intestinal wall”. They described a late phase of Crohn’s disease and did not try to reconstruct the various stages of the disease. The aim of this study is to provide a step-by-step reconstruction of the anatomic changes that lead to “terminal ileitis”, i.e., to define the pathologic process.


Methods: A pathologic examination of over 100 surgical specimens of Crohn’s disease was performed. Findings were compared with those of the published literature in order to derive sequential stages in disease evolution.


Results: Terminal ileitis occurs in four different steps. The initial event is thought to be the obstruction of the ileal branch of the superior mesenteric lymphatic collector. It leads to progressive lymphatic stasis and lymphangiectasias of all the layers of lymphatics of the intestinal wall, i.e. an intestinal lymphedema (Step 1). Progressive accumulations of protein-rich lymph occur in intestinal wall, that in the mucosa result in aphthous ulcers. The increase in pressure in the intestinal lymphatic network causes rupture of superficial lymphangiectasias (Step 2). These early parietal changes allow bacterial contamination of the lymphedema which, over time, leads to chronic superficial enteritis and granulomatous lymphangitis (Step 3). Finally, fibrosis is reached (Step 4).


Conclusions: Crohn’s disease is a lymphedema of the intestinal wall contaminated by intestinal contents, ending in fibrosis. The structural changes defy therapeutic resolution.


Keywords: Crohn’s disease, lymphedema, lymphatics

Keywords: Crohn’s disease, lymphedema, lymphatics

Article Details

How to Cite
TONELLI, Pietro. Intestinal Lymphedema and Structural Changes in Crohn's Disease. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 19 june 2024. doi:
Research Articles


1. Hadfield G. The primary histological lesion of regional ileitis. Lancet. 1939;234(6058):773-775.
doi: 10.1016/S0140-6736(00)62866-0.

2. Warren S, Sommers SC. Cicatrizing enteritis as a pathologic entity. Analysis of one hundred and twenty cases. Am J Pathol. 1948;24(3):475-501.

3. Warren S, Sommers SC. Pathology of regional ileitis and ulcerative colitis. J Am Med Ass. 1954;154(3):189-193. doi: 10.1001/jama.1954.02940370001001.

4. Mooney EE, Walker J, Hourihane DO. Relation of granulomas to lymphatic vessels in Crohn’s disease. J Clin Pathol. 1995;48(4):335-338.
doi: 10.1136/jcp.48.4.335.

5. Sundqvist T, Stenhammar L, Tjellström B, Magnusson KE, Midtvedt T, Norin E, et al. On the pathogenesis of Crohn’s disease. OBM Hepatology and Gastroenterology. 2020;4(1):4.

6. Harper PH, Lee EC, Kettlewell MG, Bennett MK, Jewell DP. Role of the faecal stream in the maintenance of Crohn’s colitis. Gut. 1985;26(3):279–284. doi: 10.1136/gut.26.3.279.

7. D’Haens GR, Geboes K, Peeters M, Baert F, Penninckx F, Rutgeerts P. Early lesions of recurrent Crohn’s disease caused by infusion of intestinal contents in excluded ileum. Gastroenterology. 1998;114(2):262–267.
doi: 10.1016/s0016-5085(98)70476-7.

8. Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986;105(6):883-885.
doi: 10.7326/0003-4819-105-6-883.

9. Odenwald MA, Turner JR. Intestinal permeability defects: is it time to treat? Clin Gastroenterol Hepatol. 2013;11(9):1075-1083.
doi: 10.1016/j.cgh.2013.07.001.

10. Van Kruiningen HJ, Ganley LM, Freda BJ. The role of Peyer’s patches in the age-related incidence of Crohn’s disease. J Clin Gastroenterology. 1997; 25(2):470-475.
doi: 10.1097/00004836-199709000-00017.

11. Bevins CL. The Paneth cell and the innate immune response. Curr Opin Gastroenterol. 2004;20(6):572-80. doi: 10.1097/00001574-200411000-00012.

12. Strober W, Zhang F, Kitani A, Fuss I, Fichtner-Feigl S. Proinflammatory cytokines underlying the inflammation of Crohn’s disease. Curr Opin Gastroenterol. 2010;26(4):310-317. doi: 10.1097/MOG.0b013e328339d099.
13. Pedica F, Ligorio C, Tonelli P, Bartolini S, Baccarini P. Lymphangiogenesis in Crohn’s disease: an immunohistochemical study using monoclonal antibody D2-40. Virchows Arch. 2008; 452(1):57-63.
doi: 10.1007/s00428-007-0540-2.

14. Daróczy J. Pathology of lymphedema. Clin Dermatol. 1995; 13(5): 433-444.
doi: 10.1016/0738-081x(95)00086-u.

15. Tonelli P. Il Linfedema dell’Intestino (Malattia di Crohn). ed. Nicola G. Napoli. Global Press S.R.L.; 2001.

16. Baert FJ, D’Haens GR, Peeters M, Hiele MI, Schaible TF, Shealy D, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn’s ileocolitis. Gastroenterology. 1999; 116(1):22–28.
doi: 10.1016/s0016-5085(99)70224-6.

17. Miller MJ, McDole JR, Newberry RD. Microanatomy of the intestinal lymphatic system. Ann N Y Acad Sci. 2010; 1207(Suppl 1):E21-E28.
doi: 10.1111/j.1749-6632.2010.05708.x.

18. Allara E, Balboni GC. Apparato della Digestione. In: L. Testut, A. Latarjet. Trattato di Anatomia Umana. 5th ed. Unione Tipografico-Editrice Torinese; Torino, 1972.

19. Hovelacque A. Les artères mésentériques. ed Doin. Paris, 1936.
20. Waldmann TA, Steinfeld J, Ditcher TF, Davidson JD, Gordon RS Jr. The role of the gastrointestinal system in “idiopathic hypoproteinemia”. Gastroenterology. 1961;41:197-207.

21. Heatley RV, Bolton PM, Hughes LE, Owen EW. Mesenteric lymphatic obstruction in Crohn’s disease. Digestion. 1980; 20(5):307-313.
doi: 10.1159/000198452.

22. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis; a pathological and clinical entity. JAMA. 1932; 99(16):1323-1329. doi:10.1001/jama.1932.02740680019005.

23. Reichert FL, Mathes ME. Experimental lymphedema of the intestinal tract and its relation to regional cicatrizing enteritis. Ann Surg. 1936;104(4):601-616.
doi: 10.1097/00000658-193610440-00013.

24. Kalima TV, Saloniemi H, Rahko T. Experimental regional enteritis in pigs. Scand J Gastroenterol. 1976;11(4):353-362.

25. Turpin W, Lee S-H, Raygoza Garay JA, Madsen KL, Meddings JB , Bedrani L, et al. Increased intestinal permeability is associated with later development of Crohn’s disease. Gastroenterology. 2020; 159(6):2092-2100.
doi: 10.1053/j.gastro.2020.08.005.

26. Kovi J, Duong HD, Hoang CT. Ultrastructure of intestinal lymphatics in Crohn’s disease. Am J Clin Pathol. 1981; 76(4):385-394. doi: 10.1093/ajcp/76.4.385.

27. Siebers A, Finlay BB. M cells and the pathogenesis of mucosal and systemic infections. Trends Microbiol. 1996; 4(1):22-29.
doi: 10.1016/0966-842x(96)81501-0.

28. Neutra MR. M cells in antigen sampling in mucosal tissues. Curr Top Microbiol Immunol. 1999; 236: 17–32.
doi: 10.1007/978-3-642-59951-4_2.

29. Kanazawa S, Tsunoda T, Onuma E, Majima T, Kagiyama M, Kikuchi K. VEGF, basic-FGF, and TGF-ß in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation. Am J Gastroenterol. 2001;96(3):822-828.
doi: 10.1111/j.1572-0241.2001.03527.x.

30. Van Kruiningen HJ, Hayes AW, Colombel J-F. Granulomas obstruct lymphatics in all layers of the intestine in Crohn’s disease. APMIS. 2014; 122(11): 1125-1129. doi: 10.1111/apm.12268.

31. Van Kruiningen H. Missing the target to treat in Crohn’s disease. OBM Hepatology and Gastroenterology. 2019;3(3):7.
doi: 10.21926/obm.hg.1903036.

32. Knutson H, Lunderquist A, Lunderquist A. Vascular changes in Crohn’s disease. Am J Roentgenol. 1968;103(2):380-385. doi: 10.2214/ajr.103.2.380.

33. Wakefield AJ, Sawyerr AM, Dhillon AP, Pittilo RM, Rowles PM, Lewis AA, et al. Pathogenesis of Crohn’s disease: Multifocal gastrointestinal infarction. Lancet. 1989;2(8671):1057-1062. doi: 10.1016/s0140-6736(89)91078-7.

34. Tonelli P, Martellucci J, Lucchese M, Comin CE, Bergamini C, Pedica F, et al. Preliminary results of the influence of the in vivo use of a lymphatic dye (Patent Blue V) in the surgical treatment of Crohn's disease. Surg Innov. 2014; 21(4):381-388.
doi: 10.1177/1553350613508017.

35. Graham MF, Diegelmann RF, Elson CO, Lindblad WJ, Gotschalk N, Gay S, et al. Collagen content and types in the intestinal strictures of Crohn’s disease. Gastroenterology. 1988; 94(2):257-265. doi: 10.1016/0016-5085(88)90411-8.

36. von der Weid PY, Rehal S, Ferraz JG. Role of the lymphatic system in the pathogenesis of Crohn’s disease. Curr Opin Gastroenterol. 2011;27(4):335-341. doi: 10.1097/MOG.0b013e3283476e8f.

37. Dvorak AM, Osage JE, Monahan RA, Dickersin GR. Crohn’s disease: transmission electron microscopic studies. III. Target tissues. Proliferation of and injury to smooth muscle and the autonomic nervous system. Hum Pathol. 1980;11(6):620–634.
doi: 10.1016/s0046-8177(80)80073-6.

38. Ferrante M, De Hertogh G, Hlavaty T, D’Haens G, Penninckx F, D’Hoore A, et al. The value of myenteric plexitis to predict early postoperative Crohn’s disease recurrence. Gastroenterology. 2006;130(6):1595–1606.
doi: 10.1053/j.gastro.2006.02.025.

39. Ng SC, Lied GA, Kamm MA, Sandhu F, Guenther T, Arebi N. Predictive value and clinical significance of myenteric plexitis in Crohn’s disease. Inflamm Bowel Dis. 2009; 15(10):1499-1507.
doi: 10.1002/ibd.20932.

40. Severi C, Sferra R, Scirocco A, Vetuschi A, Pallotta N, Pronio A, et al. Contribution of intestinal smooth muscle to Crohn’s disease fibrogenesis. Eur J Histochem. 2014; 58(4): 2457.
doi: 10.4081/ejh.2014.2457.

41. Van Kruiningen H. An infectious pig model of Crohn’s disease. Inflamm Bowel Dis. 2016; 22(9): 2106-2111. doi: 10.1097/MIB.0000000000000831.

42. Cook MG. The size and histological appearances of mesenteric lymph nodes in Crohn’s disease. Gut. 1972;13(12):970-972.
doi: 10.1136/gut.13.12.970.

43. Szuba A, Rockson SG. Lymphedema: classification, diagnosis and therapy. Vasc Med. 1998; 3(12):145-156.
doi: 10.1177/1358836X9800300209.