Abstract
Anal fistulas continue to be a problem for patients and surgeons alike despite scientific advances. While patient and anatomical characteristics are important to surgeons who are evaluating patients with anal fistulas, their development and persistence likely involves a multifaceted interaction of histological, microbiological, and molecular factors. Histological studies have shown that anal fistulas are variably epithelialized and are surrounded by dense collagen tissue with pockets of inflammatory cells. Yet, it remains unknown if or how histological differences impact fistula healing. The presence of a perianal abscess that contains gut flora commonly leads to the development of anal fistula. This implies a microbiological component, but bacteria are infrequently found in chronic fistulas. Recent work has shown an increased expression of proinflammatory cytokines and epithelial to mesenchymal cell transition in both cryptoglandular and Crohn’s perianal fistulas. This suggests that molecular mechanisms may also play a role in both fistula development and persistence. The aim of this study was to examine the histological, microbiological, molecular, and host factors that contribute to the development and persistence of anal fistulas.
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References
Abcarian H (2014) Anal fistula principles and management. Springer, New York
Nelson R (2002) Anorectal abscess fistula: what do we know? Surg Clin North Am 82(6):1139–1151 (v–vi)
Sainio P (1984) Fistula-in-ano in a defined population. Incidence and epidemiological aspects. Ann Chir Gynaecol 73(4):219–224
Kronborg O (1985) To lay open or excise a fistula-in-ano: a randomized trial. Br J Surg 72(12):970
Hebjorn M, Olsen O, Haakansson T, Andersen B (1987) A randomized trial of fistulotomy in perianal abscess. Scand J Gastroenterol 22(2):174–176
Tang CL, Chew SP, Seow-Choen F (1996) Prospective randomized trial of drainage alone vs. drainage and fistulotomy for acute perianal abscesses with proven internal opening. Dis Colon Rectum 39(12):1415–1417
Ho YH, Tan M, Chui CH, Leong A, Eu KW, Seow-Choen F (1997) Randomized controlled trial of primary fistulotomy with drainage alone for perianal abscesses. Dis Colon Rectum 40(12):1435–1438
Ho YH, Tan M, Leong AF, Seow-Choen F (1998) Marsupialization of fistulotomy wounds improves healing: a randomized controlled trial. Br J Surg 85(1):105–107. doi:10.1046/j.1365-2168.1998.00529.x
Oliver I, Lacueva FJ, Perez Vicente F, Arroyo A, Ferrer R, Cansado P, Candela F, Calpena R (2003) Randomized clinical trial comparing simple drainage of anorectal abscess with and without fistula track treatment. Int J Colorectal Dis 18(2):107–110. doi:10.1007/s00384-002-0429-0
Pescatori M, Ayabaca SM, Cafaro D, Iannello A, Magrini S (2006) Marsupialization of fistulotomy and fistulectomy wounds improves healing and decreases bleeding: a randomized controlled trial. Colorectal Dis 8(1):11–14. doi:10.1111/j.1463-1318.2005.00835.x
Garcia-Aguilar J, Belmonte C, Wong WD, Goldberg SM, Madoff RD (1996) Anal fistula surgery. Factors associated with recurrence and incontinence. Dis Colon Rectum 39(7):723–729
Abbas MA, Jackson CH, Haigh PI (2011) Predictors of outcome for anal fistula surgery. Arch Surg 146(9):1011–1016. doi:10.1001/archsurg.2011.197
van Onkelen RS, Gosselink MP, Thijsse S, Schouten WR (2014) Predictors of outcome after transanal advancement flap repair for high transsphincteric fistulas. Dis Colon Rectum 57(8):1007–1011. doi:10.1097/DCR.0000000000000154
Mitalas LE, Dwarkasing RS, Verhaaren R, Zimmerman DD, Schouten WR (2011) Is the outcome of transanal advancement flap repair affected by the complexity of high transsphincteric fistulas? Dis Colon Rectum 54(7):857–862. doi:10.1007/DCR.0b013e31820eee2e
Cintron JR, Park JJ, Orsay CP, Pearl RK, Nelson RL, Sone JH, Song R, Abcarian H (2000) Repair of fistulas-in-ano using fibrin adhesive: long-term follow-up. Dis Colon Rectum 43(7):944–949 (discussion 949–950)
Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16(5):585–601. doi:10.1111/j.1524-475X.2008.00410.x
Guo S, Dipietro LA (2010) Factors affecting wound healing. J Dent Res 89(3):219–229. doi:10.1177/0022034509359125
Ramanujam PS, Prasad ML, Abcarian H, Tan AB (1984) Perianal abscesses and fistulas. A study of 1023 patients. Dis Colon Rectum 27(9):593–597
Chrabot CM, Prasad ML, Abcarian H (1983) Recurrent anorectal abscesses. Dis Colon Rectum 26(2):105–108
Hamadani A, Haigh PI, Liu IL, Abbas MA (2009) Who is at risk for developing chronic anal fistula or recurrent anal sepsis after initial perianal abscess? Dis Colon Rectum 52(2):217–221. doi:10.1007/DCR.0b013e31819a5c52
Devaraj B, Khabassi S, Cosman BC (2011) Recent smoking is a risk factor for anal abscess and fistula. Dis Colon Rectum 54(6):681–685. doi:10.1007/DCR.0b013e31820e7c7a
Read DR, Abcarian H (1979) A prospective survey of 474 patients with anorectal abscess. Dis Colon Rectum 22(8):566–568
McColl I (1967) The comparative anatomy and pathology of anal glands. Arris and Gale lecture delivered at the Royal College of Surgeons of England on 25th February 1965. Ann R Coll Surg Engl 40(1):36–67
El-Tawil AM (2012) Mechanism of non-specific-fistula-in-ano: hormonal aspects—review. Pathophysiology 19(1):55–59. doi:10.1016/j.pathophys.2011.07.004
Phillips RKS, Clark S (2014) Colorectal surgery. Companion to specialist surgical practice, 5th edn. Saunders/Elsevier, Edinburgh
Wang D, Yang G, Qiu J, Song Y, Wang L, Gao J, Wang C (2014) Risk factors for anal fistula: a case-control study. Tech Coloproctol 18(7):635–639. doi:10.1007/s10151-013-1111-y
Seow-Choen F, Ho JM (1994) Histoanatomy of anal glands. Dis Colon Rectum 37(12):1215–1218
Parks AG (1961) Pathogenesis and treatment of fistuila-in-ano. Br Med J 1(5224):463–469
Herrmann GD, Desfosses L (1880) La sur la muquese de la region cloacle du rectum. CR Acad Sci 111(90):1301–1302
Eykyn SJ, Grace RH (1986) The relevance of microbiology in the management of anorectal sepsis. Ann R Coll Surg Engl 68(5):237–239
Toyonaga T, Matsushima M, Tanaka Y, Shimojima Y, Matsumura N, Kannyama H, Nozawa M, Hatakeyama T, Suzuki K, Yanagita K, Tanaka M (2007) Microbiological analysis and endoanal ultrasonography for diagnosis of anal fistula in acute anorectal sepsis. Int J Colorectal Dis 22(2):209–213. doi:10.1007/s00384-006-0121-x
Vogel JD, Johnson EK, Morris AM, Paquette IM, Saclarides TJ, Feingold DL, Steele SR (2016) Clinical practice guideline for the management of anorectal abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum 59(12):1117–1133. doi:10.1097/DCR.0000000000000733
Magalhaes JG, Tattoli I, Girardin SE (2007) The intestinal epithelial barrier: how to distinguish between the microbial flora and pathogens. Semin Immunol 19(2):106–115. doi:10.1016/j.smim.2006.12.006
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007
Bataille F, Rohrmeier C, Bates R, Weber A, Rieder F, Brenmoehl J, Strauch U, Farkas S, Furst A, Hofstadter F, Scholmerich J, Herfarth H, Rogler G (2008) Evidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn’s disease. Inflamm Bowel Dis 14(11):1514–1527. doi:10.1002/ibd.20590
Scharl M, Rogler G (2014) Pathophysiology of fistula formation in Crohn’s disease. World J Gastrointest Pathophysiol 5(3):205–212. doi:10.4291/wjgp.v5.i3.205
Hofman P, Vouret-Craviari V (2012) Microbes-induced EMT at the crossroad of inflammation and cancer. Gut Microbes 3(3):176–185. doi:10.4161/gmic.20288
Yadav V, Varum F, Bravo R, Furrer E, Bojic D, Basit AW (2016) Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 176:38–68. doi:10.1016/j.trsl.2016.04.009
Ratto C, Litta F, Lucchetti D, Parello A, Boninsegna A, Arena V, Donisi L, Calapa F, Sgambato A (2016) Immunopathological characterization of cryptoglandular anal fistula: a pilot study investigating its pathogenesis. Colorectal Dis 18(12):O436–O444. doi:10.1111/codi.13527
van Koperen PJ, Wind J, Bemelman WA, Bakx R, Reitsma JB, Slors JF (2008) Long-term functional outcome and risk factors for recurrence after surgical treatment for low and high perianal fistulas of cryptoglandular origin. Dis Colon Rectum 51(10):1475–1481. doi:10.1007/s10350-008-9354-9
Gustafsson UM, Graf W (2006) Randomized clinical trial of local gentamicin-collagen treatment in advancement flap repair for anal fistula. Br J Surg 93(10):1202–1207. doi:10.1002/bjs.5398
Sonoda T, Hull T, Piedmonte MR, Fazio VW (2002) Outcomes of primary repair of anorectal and rectovaginal fistulas using the endorectal advancement flap. Dis Colon Rectum 45(12):1622–1628. doi:10.1097/01.DCR.0000037653.68665.E8
Zimmerman DD, Briel JW, Gosselink MP, Schouten WR (2001) Anocutaneous advancement flap repair of transsphincteric fistulas. Dis Colon Rectum 44(10):1474–1480
Sirikurnpiboon S, Awapittaya B, Jivapaisarnpong P (2013) Ligation of intersphincteric fistula tract and its modification: results from treatment of complex fistula. World J Gastrointest Surg 5(4):123–128. doi:10.4240/wjgs.v5.i4.123
Zimmerman DD, Delemarre JB, Gosselink MP, Hop WC, Briel JW, Schouten WR (2003) Smoking affects the outcome of transanal mucosal advancement flap repair of trans-sphincteric fistulas. Br J Surg 90(3):351–354. doi:10.1002/bjs.4044
Ellis CN, Clark S (2007) Effect of tobacco smoking on advancement flap repair of complex anal fistulas. Dis Colon Rectum 50(4):459–463. doi:10.1007/s10350-006-0829-2
Ellis CN, Rostas JW, Greiner FG (2010) Long-term outcomes with the use of bioprosthetic plugs for the management of complex anal fistulas. Dis Colon Rectum 53(5):798–802. doi:10.1007/DCR.0b013e3181d43b7d
Abcarian AM, Estrada JJ, Park J, Corning C, Chaudhry V, Cintron J, Prasad L, Abcarian H (2012) Ligation of intersphincteric fistula tract: early results of a pilot study. Dis Colon Rectum 55(7):778–782. doi:10.1097/DCR.0b013e318255ae8a
Seow-Choen F, Hay AJ, Heard S, Phillips RK (1992) Bacteriology of anal fistulae. Br J Surg 79(1):27–28
Lunniss PJ, Faris B, Rees HC, Heard S, Phillips RK (1993) Histological and microbiological assessment of the role of microorganisms in chronic anal fistula. Br J Surg 80(8):1072
de San Ildefonso PA, Maruri CI, Facal AC, Torres J, Casal JE (2002) Bacteriology of anal fistulae. Rev Esp Enferm Dig 94(9):533–536
Tozer PJ, Rayment N, Hart AL, Daulatzai N, Murugananthan AU, Whelan K, Phillips RK (2015) What role do bacteria play in persisting fistula formation in idiopathic and Crohn’s anal fistula? Colorectal Dis 17(3):235–241. doi:10.1111/codi.12810
van Onkelen RS, Mitalas LE, Gosselink MP, van Belkum A, Laman JD, Schouten WR (2013) Assessment of microbiota and peptidoglycan in perianal fistulas. Diagn Microbiol Infect Dis 75(1):50–54. doi:10.1016/j.diagmicrobio.2012.09.012
Kiehne K, Fincke A, Brunke G, Lange T, Folsch UR, Herzig KH (2007) Antimicrobial peptides in chronic anal fistula epithelium. Scand J Gastroenterol 42(9):1063–1069. doi:10.1080/00365520701320489
van Onkelen RS, Gosselink MP, van Meurs M, Melief MJ, Schouten WR, Laman JD (2016) Pro-inflammatory cytokines in cryptoglandular anal fistulas. Tech Coloproctol 20(9):619–625. doi:10.1007/s10151-016-1494-7
Plevy SE, Landers CJ, Prehn J, Carramanzana NM, Deem RL, Shealy D, Targan SR (1997) A role for TNF-alpha and mucosal T helper-1 cytokines in the pathogenesis of Crohn’s disease. J Immunol 159(12):6276–6282
Marzo M, Felice C, Pugliese D, Andrisani G, Mocci G, Armuzzi A, Guidi L (2015) Management of perianal fistulas in Crohn’s disease: an up-to-date review. World J Gastroenterol 21(5):1394–1403. doi:10.3748/wjg.v21.i5.1394
Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner BA, Onken JE, Rachmilewitz D, Rutgeerts P, Wild G, Wolf DC, Marsters PA, Travers SB, Blank MA, van Deventer SJ (2004) Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 350(9):876–885. doi:10.1056/NEJMoa030815
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF (2007) Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology 132(1):52–65. doi:10.1053/j.gastro.2006.11.041
Schreiber S, Lawrance IC, Thomsen OO, Hanauer SB, Bloomfield R, Sandborn WJ (2011) Randomised clinical trial: certolizumab pegol for fistulas in Crohn’s disease—subgroup results from a placebo-controlled study. Aliment Pharmacol Ther 33(2):185–193. doi:10.1111/j.1365-2036.2010.04509.x
Kubota M, Hirayama Y, Okuyama N (2010) Usefulness of bFGF spray in the treatment of perianal abscess and fistula-in-ano. Pediatr Surg Int 26(10):1037–1040. doi:10.1007/s00383-010-2664-8
Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M (2009) Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 52(1):79–86. doi:10.1007/DCR.0b013e3181973487
Molendijk I, Bonsing BA, Roelofs H, Peeters KC, Wasser MN, Dijkstra G, van der Woude CJ, Duijvestein M, Veenendaal RA, Zwaginga JJ, Verspaget HW, Fibbe WE, van der Meulen-de Jong AE, Hommes DW (2015) Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Promote Healing of Refractory Perianal Fistulas in Patients With Crohn’s Disease. Gastroenterology 149 (4):918-927 e916. doi:10.1053/j.gastro.2015.06.014
Panes J, Garcia-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, Dignass A, Nachury M, Ferrante M, Kazemi-Shirazi L, Grimaud JC, de la Portilla F, Goldin E, Richard MP, Leselbaum A, Danese S, Collaborators ACSG (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388(10051):1281–1290. doi:10.1016/S0140-6736(16)31203-X
Panes J (2016) Stem cell therapy for perianal fistulas in crohn’s disease. Gastroenterol Hepatol (N Y) 12(10):637–640
Singer NG, Caplan AI (2011) Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 6:457–478. doi:10.1146/annurev-pathol-011110-130230
DelaRosa O, Dalemans W, Lombardo E (2012) Mesenchymal stem cells as therapeutic agents of inflammatory and autoimmune diseases. Curr Opin Biotechnol 23(6):978–983. doi:10.1016/j.copbio.2012.05.005
Whitehead SM, Leach RD, Eykyn SJ, Phillips I (1982) The aetiology of perirectal sepsis. Br J Surg 69(3):166–168
Grace RH, Harper IA, Thompson RG (1982) Anorectal sepsis: microbiology in relation to fistula-in-ano. Br J Surg 69(7):401–403
Henrichsen S, Christiansen J (1986) Incidence of fistula-in-ano complicating anorectal sepsis: a prospective study. Br J Surg 73(5):371–372
Lunniss PJ, Phillips RK (1994) Surgical assessment of acute anorectal sepsis is a better predictor of fistula than microbiological analysis. Br J Surg 81(3):368–369
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Sugrue, J., Nordenstam, J., Abcarian, H. et al. Pathogenesis and persistence of cryptoglandular anal fistula: a systematic review. Tech Coloproctol 21, 425–432 (2017). https://doi.org/10.1007/s10151-017-1645-5
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DOI: https://doi.org/10.1007/s10151-017-1645-5