Toxic megacolon pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]
Overview
Toxic megacolon results from severe inflammation extending into the smooth-muscle layer and paralyses the colonic smooth muscle leading to dilatation. The extent of dilatation associated with the depth of inflammation and ulceration. Nitric oxide, an inhibitor of smooth-muscle tone, has an important role in the pathogenesis of toxic megacolon. Nitric oxide is produced by neutrophils and smooth-muscle cells in the inflamed colon.
Pathophysiology
Pathogenesis
The following flowchart outlines the main mechanisms leading to the development of toxic megacolon, the explanation follows:[1][2][3]
Flowchart showing pathogenesis of toxic megacolon[2]
| Neutrophils | |||||||||||||||||||||||||||||||||||||
| Invade ulcerated mucosa | Invade muscle layers | Release nitric oxide(NO) | |||||||||||||||||||||||||||||||||||
| Cyrpt abcess and diffuse colitis | Release cytokines, leukotriene B4 (LTB4), proteolytic enzymes | Paralysis muscle cells | |||||||||||||||||||||||||||||||||||
| Directly damage muscle cells | Systemic uptake of cytokines and other inflammatory mediators | Dilation | |||||||||||||||||||||||||||||||||||
| Fever, hypotension, tachycardia | |||||||||||||||||||||||||||||||||||||
| Toxic megacolon | |||||||||||||||||||||||||||||||||||||
Intestinal smooth muscle contractility
- There is a strong association between inflammatory conditions of the colon and decreased smooth muscle contractility.[4][5]
- The influx of calcium (Ca2+) through voltage-dependent L-type Ca2+ channels plays a central role in the initiation of contraction.[5]
- The calcium binds to calmodulin intracellulary, leading to the formation of calcium-calmodulin complex.
- The calcium calmodulin complex activates myosin light chain kinase.
- Myosin light chain kinase phosphorylates myosin light chain 20 and leads to cross-linking between actin filaments and myosin head causing smooth muscle contraction.
Role of smooth muscles in inflammatory conditions
- Smooth muscle cells carry receptors for numerous cytokines and chemokines, which are produced during inflammation.[6]
- These cytokines and chemokines may lead to alteration in the ionic concentration of the cells (which includes the concentration of calcium ions).[7]
- The end result is a decrease in smooth muscle contractility (hypocontractility).
- The decreased contractility increases the gastrointestinal transit time, thereby providing a good environment for bacterial overgrowth.
Smooth muscle contraction in toxic megacolon
- It is believed that toxic megacolon is the result of defective smooth muscle contraction, decreased basal pressure in the colonic lumen, and an inhibited gastro-colic reflex is caused by changes in colonic response to vasoactive intestinal polypeptide, substance P, neurotensin, leukotrienes, and nitric oxide.[8][9][10][11]
Role of nitric oxide (NO)
- The progression of inflammatory bowel disease to toxic megacolon is usually caused by soluble inflammatory mediators, that has downstream inhibitory effects on colonic muscle tone. Nitric oxide is the the most important non-adrenergic, non-cholinergic neurotransmitter that induces colonic smooth muscle relaxation.[11][12][2][3][13][9]
Progression of toxic megacolon
- The inflammatory process in toxic megacolon extends up to muscularis propria when compared to uncomplicated ulcerative colitis (limited to superfacial layer of submucosa).[14][15][16]
- The depth of inflammation is known to correlate with the extent of colonic dilatation.[2][17][18]
Associated Conditions
Conditions associated with toxic megacolon include:[19][20][21][22][23]
- Inflammatory bowel disease
- Clostridium difficile pseudomembranous enterocolitis
- Ischemia enterocolitis
- Methotrexate therapy
- Colon cancer
Gross Pathology
- Gross pathology of toxic megacolon include:[24][25]
- Dilated colon
- Eroded mucosa
- Diffuse ulcerations
- Raised mucosal nodules
- Yellowish-white superficial plaques with normal intervening mucosa (typical pseudomembrane appearance)
- Extensive denudation
Microscopic Pathology
- Microscopic histopathological analysis include:[2]
- Transmural acute inflammation of colon
- Necrosis
- Replacement by granulation tissue infiltrated by histiocytes, neutrophils, lymphocytes, and plasma cells
- Shortened and rounded muscle with aggregates of eosinophilic cytoplasm
- Preserved colonic submucosal and myenteric plexuses
References
- ↑ Mourelle M, Vilaseca J, Guarner F, Salas A, Malagelada JR (1996). "Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase". Am. J. Physiol. 270 (3 Pt 1): G425–30. PMID 8638708.
- ↑ 2.0 2.1 2.2 2.3 2.4 Sheth SG, LaMont JT (1998). "Toxic megacolon". Lancet. 351 (9101): 509–13. doi:10.1016/S0140-6736(97)10475-5. PMID 9482465.
- ↑ 3.0 3.1 Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada JR (1995). "Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon". Gastroenterology. 109 (5): 1497–502. PMID 7557131.
- ↑ Ohama T, Hori M, Ozaki H (2007). "Mechanism of abnormal intestinal motility in inflammatory bowel disease: how smooth muscle contraction is reduced?". J Smooth Muscle Res. 43 (2): 43–54. PMID 17598957.
- ↑ 5.0 5.1 Shea-Donohue T, Notari L, Sun R, Zhao A (2012). "Mechanisms of smooth muscle responses to inflammation". Neurogastroenterol. Motil. 24 (9): 802–11. doi:10.1111/j.1365-2982.2012.01986.x. PMC 4068333. PMID 22908862.
- ↑ Sethi AK, Sarna SK (1991). "Colonic motor activity in acute colitis in conscious dogs". Gastroenterology. 100 (4): 954–63. PMID 2001831.
- ↑ Mawe GM, Collins SM, Shea-Donohue T (2004). "Changes in enteric neural circuitry and smooth muscle in the inflamed and infected gut". Neurogastroenterol. Motil. 16 Suppl 1: 133–6. doi:10.1111/j.1743-3150.2004.00489.x. PMID 15066019.
- ↑ Template:Citejournal
- ↑ 9.0 9.1 Gan, S. Ian; Beck, P. L. (2003). "A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management". The American Journal of Gastroenterology. 98 (11): 2363–2371. doi:10.1111/j.1572-0241.2003.07696.x. ISSN 0002-9270.
- ↑ Norland CC, Kirsner JB (1969). "Toxic dilatation of colon (toxic megacolon): etiology, treatment and prognosis in 42 patients". Medicine (Baltimore). 48 (3): 229–50. PMID 5769743.
- ↑ 11.0 11.1 Latella G, Vernia P, Viscido A, Frieri G, Cadau G, Cocco A, Cossu A, Tomei E, Caprilli R (2002). "GI distension in severe ulcerative colitis". Am. J. Gastroenterol. 97 (5): 1169–75. doi:10.1111/j.1572-0241.2002.05691.x. PMID 12014723.
- ↑ Boeckxstaens GE, Pelckmans PA, Herman AG, Van Maercke YM (1993). "Involvement of nitric oxide in the inhibitory innervation of the human isolated colon". Gastroenterology. 104 (3): 690–7. PMID 8095033.
- ↑ Schwörer H, Bohn M, Waezsada SY, Raddatz D, Ramadori G (2001). "Successful treatment of megacolon associated with colitis with a nitric oxide synthase inhibitor". Am. J. Gastroenterol. 96 (7): 2273–4. doi:10.1111/j.1572-0241.2001.03986.x. PMID 11467676.
- ↑ Buckell NA, Williams GT, Bartram CI, Lennard-Jones JE (1980). "Depth of ulceration in acute colitis: correlation with outcome and clinical and radiologic features". Gastroenterology. 79 (1): 19–25. PMID 7380218.
- ↑ Rosenberg M (1976). "Toxic megacolon". West. J. Med. 124 (2): 122–7. PMC 1130453. PMID 1246881.
- ↑ Danovitch SH (1989). "Fulminant colitis and toxic megacolon". Gastroenterol. Clin. North Am. 18 (1): 73–82. PMID 2493427.
- ↑ Akbarali HI, Kang M (2015). "Postranslational Modification of Ion Channels in Colonic Inflammation". Curr Neuropharmacol. 13 (2): 234–8. PMC 4598435. PMID 26411766.
- ↑ Bassotti G, Antonelli E, Villanacci V, Salemme M, Coppola M, Annese V (2014). "Gastrointestinal motility disorders in inflammatory bowel diseases". World J. Gastroenterol. 20 (1): 37–44. doi:10.3748/wjg.v20.i1.37. PMC 3886030. PMID 24415856.
- ↑ Grieco MB, Bordan DL, Geiss AC, Beil AR (1980). "Toxic megacolon complicating Crohn's colitis". Ann. Surg. 191 (1): 75–80. PMC 1344622. PMID 7352781.
- ↑ Autenrieth DM, Baumgart DC (2012). "Toxic megacolon". Inflamm. Bowel Dis. 18 (3): 584–91. doi:10.1002/ibd.21847. PMID 22009735.
- ↑ Autenrieth, Daniel M.; Baumgart, Daniel C. (2012). "Toxic megacolon". Inflammatory Bowel Diseases. 18 (3): 584–591. doi:10.1002/ibd.21847. ISSN 1078-0998.
- ↑ SILVERBERG D, ROGERS AG (1964). "TOXIC MEGACOLON IN ULCERATIVE COLITIS". Can Med Assoc J. 90: 357–63. PMC 1922240. PMID 14122466.
- ↑ Collier, Richard L.; Wylie, John H.; Gomez, Jorge (1971). "Toxic megacolon". The American Journal of Surgery. 121 (3): 283–288. doi:10.1016/0002-9610(71)90205-4. ISSN 0002-9610.
- ↑ Kobayasi S, Mendes EF, Rodrigues MA, Franco MF (1992). "Toxic dilatation of the colon in Chagas' disease". Br J Surg. 79 (11): 1202–3. PMID 1467905.
- ↑ Seltman AK (2012). "Surgical Management of Clostridium difficile Colitis". Clin Colon Rectal Surg. 25 (4): 204–9. doi:10.1055/s-0032-1329390. PMC 3577611. PMID 24294121.