International Journal of Colorectal Disease

, Volume 24, Issue 12, pp 1389–1394 | Cite as

Haemorrhoids are related to changes of cell function in mucosa and submucosa

  • Christian KlinkEmail author
  • Marcel Binnebösel
  • Daniel Kämmer
  • Stefan Willis
  • Andreas Prescher
  • Uwe Klinge
  • Volker Schumpelick
Original Article



Epidemiology and risk factors of haemorrhoidal disease are not well defined. This study tried to evaluate if the appearance of haemorrhoids is related to a disturbed remodelling of the soft tissue of rectal mucosa and submucosa. Therefore, immunohistochemical expression profiles of five parameters as potential mediators in neoangiogenesis (EGFR), in inflammatory cell activity (COX-2), and in cell migration, differentiation, and wound healing (notch-3, c-myc, and ß-Catenin) were analysed (Saed et al., Fertil Steril 83(Suppl 1):1216–1219, 1; Saed et al., Fertil Steril 79:1404–1408, 2; Stojadinovic et al., Am J Pathol 167:59–69, 3).


Haemorrhoidal tissue specimens were collected from 44 patients. Healthy rectal mucosa was obtained from 16 non-fixed fresh cadavers and served as control. Histological and immunohistochemical markers like EGFR, COX-2, notch-3, c-myc, and ß-Catenin were analysed semi-quantitatively, separately for mucosal and submucosal layer.


Significantly increased expressions were found for EGFR, COX-2, and notch-3 in the mucosal and submucosal layer of haemorrhoidal tissue in comparison to normal rectal tissue.


This finding confirms that haemorrhoidal disease may be regarded as a manifestation of a soft tissue disease.


Haemorrhoids Extracellular matrix Pathogenesis Wound healing 



We are grateful to Mrs. Ellen Krott for most excellent and careful assistance during this investigation.


  1. 1.
    Saed GM, Munkarah AR, bu-Soud HM, Diamond MP (2005) Hypoxia upregulates cyclooxygenase-2 and prostaglandin E(2) levels in human peritoneal fibroblasts. Fertil Steril 83(Suppl 1):1216–1219CrossRefPubMedGoogle Scholar
  2. 2.
    Saed GM, Munkarah AR, Diamond MP (2003) Cyclooxygenase-2 is expressed in human fibroblasts isolated from intraperitoneal adhesions but not from normal peritoneal tissues. Fertil Steril 79:1404–1408CrossRefPubMedGoogle Scholar
  3. 3.
    Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J, Stallcup M, Merchant A, Galiano RD, Tomic-Canic M (2005) Molecular pathogenesis of chronic wounds: the role of beta-catenin and c-myc in the inhibition of epithelialization and wound healing. Am J Pathol 167:59–69PubMedGoogle Scholar
  4. 4.
    Delco F, Sonnenberg A (1998) Associations between hemorrhoids and other diagnoses. Dis Colon Rectum 41:1534–1541CrossRefPubMedGoogle Scholar
  5. 5.
    Burkitt DP (1973) Varicose veins, deep vein thrombosis, and hemorrhoids. Am Heart J 85:572–573CrossRefPubMedGoogle Scholar
  6. 6.
    Johanson JF, Sonnenberg A (1990) The prevalence of hemorrhoids and chronic constipation. An epidemiologic study. Gastroenterology 98:380–386PubMedGoogle Scholar
  7. 7.
    Thomson WH (1975) The nature of haemorrhoids. Br J Surg 62:542–552CrossRefPubMedGoogle Scholar
  8. 8.
    Lierse W (1989) Anatomy and pathophysiology of hemorrhoids. Langenbecks Arch Chir Suppl II Verh Dtsch Ges Chir 769–772Google Scholar
  9. 9.
    Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe 8:138–140PubMedGoogle Scholar
  10. 10.
    Haas PA, Fox TA Jr, Haas GP (1984) The pathogenesis of hemorrhoids. Dis Colon Rectum 27:442–450CrossRefPubMedGoogle Scholar
  11. 11.
    Stelzner F (1998) Chirurgie an den viszeralen Abschlusssystemen. Thieme, StuttgartGoogle Scholar
  12. 12.
    Tokumaru S, Higashiyama S, Endo T, Nakagawa T, Miyagawa JI, Yamamori K, Hanakawa Y, Ohmoto H, Yoshino K, Shirakata Y, Matsuzawa Y, Hashimoto K, Taniguchi N (2000) Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. J Cell Biol 151:209–220CrossRefPubMedGoogle Scholar
  13. 13.
    Martin P (1997) Wound healing—aiming for perfect skin regeneration. Science 276:75–81CrossRefPubMedGoogle Scholar
  14. 14.
    Minghetti L, Polazzi E, Nicolini A, Creminon C, Levi G (1997) Up-regulation of cyclooxygenase-2 expression in cultured microglia by prostaglandin E2, cyclic AMP and non-steroidal anti-inflammatory drugs. Eur J Neurosci 9:934–940CrossRefPubMedGoogle Scholar
  15. 15.
    Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188PubMedGoogle Scholar
  16. 16.
    DuBois RN, Tsujii M, Bishop P, Awad JA, Makita K, Lanahan A (1994) Cloning and characterization of a growth factor-inducible cyclooxygenase gene from rat intestinal epithelial cells. Am J Physiol 266:G822–G827PubMedGoogle Scholar
  17. 17.
    DuBois RN, Awad J, Morrow J, Roberts LJ, Bishop PR (1994) Regulation of eicosanoid production and mitogenesis in rat intestinal epithelial cells by transforming growth factor-alpha and phorbol ester. J Clin Invest 93:493–498CrossRefPubMedGoogle Scholar
  18. 18.
    Tordjman C, Coge F, Andre N, Rique H, Spedding M, Bonnet J (1995) Characterisation of cyclooxygenase 1 and 2 expression in mouse resident peritoneal macrophages in vitro; interactions of non steroidal anti-inflammatory drugs with COX2. Biochim Biophys Acta 1256:249–256PubMedGoogle Scholar
  19. 19.
    Siegler AM, Kontopoulos V, Wang CF (1980) Prevention of postoperative adhesions in rabbits with ibuprofen, a nonsteroidal anti-inflammatory agent. Fertil Steril 34:46–49PubMedGoogle Scholar
  20. 20.
    Cofer KF, Himebaugh KS, Gauvin JM, Hurd WW (1994) Inhibition of adhesion reformation in the rabbit model by meclofenamate: an inhibitor of both prostaglandin and leukotriene production. Fertil Steril 62:1262–1265PubMedGoogle Scholar
  21. 21.
    Rodgers KE, Girgis W, Campeau JD, diZerega GS (1997) Reduction of adhesion formation by intraperitoneal administration of anti-inflammatory peptide 2. J Invest Surg 10:31–36PubMedCrossRefGoogle Scholar
  22. 22.
    Hayward SD, Liu J, Fujimuro M (2006) Notch and Wnt signaling: mimicry and manipulation by gamma herpesviruses. Sci STKE 2006(335):re4CrossRefPubMedGoogle Scholar
  23. 23.
    Rodewald HR (2006) Making a notch in the lymphocyte kit. Eur J Immunol 36:508–511CrossRefPubMedGoogle Scholar
  24. 24.
    Spevak SE, Shekhter AB, Hilse H, Oehme P, Solov’eva AI (1989) Characteristics of the course of the wound process in spontaneously hypertensive rats and the effect of morphine, substance P and its fragment SP1–4. Biull Eksp Biol Med 107:739–743PubMedGoogle Scholar
  25. 25.
    Isogai N, Fujii S, Tsukahara T, Kamiishi H (1993) Effect of hypertension on arterial structure and wound repair at the microvascular anastomosis site using stroke-prone spontaneously hypertensive rats (SHRSP). Microsurgery 14:501–507CrossRefPubMedGoogle Scholar
  26. 26.
    Misra V, Misra SP, Dwivedi M, Singh PA, Kumar V (2003) Colonic mucosa in patients with portal hypertension. J Gastroenterol Hepatol 18:302–308CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Christian Klink
    • 1
    Email author
  • Marcel Binnebösel
    • 1
  • Daniel Kämmer
    • 1
  • Stefan Willis
    • 2
  • Andreas Prescher
    • 3
  • Uwe Klinge
    • 1
    • 4
  • Volker Schumpelick
    • 1
  1. 1.Department of SurgeryRWTH Aachen University HospitalAachenGermany
  2. 2.Department of SurgeryKlinikum Ludwigshafen/RheinLudwigshafenGermany
  3. 3.Institute of Anatomy and Cell Biology, RWTH AachenAachenGermany
  4. 4.Applied Medical EngineeringHelmholtz Institut, RWTH AachenAachenGermany

Personalised recommendations