Toxic megacolon pathophysiology: Difference between revisions

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==Overview==
==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.
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|ulceratio]]<nowiki/>n. [[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==
==Pathophysiology==


===Pathogenesis===
===Pathogenesis===
The following flowchart outlines the main mechanisms leading to the development of toxic megacolon, the explanation follows:<ref name="pmid8638708">{{cite journal |vauthors=Mourelle M, Vilaseca J, Guarner F, Salas A, Malagelada JR |title=Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase |journal=Am. J. Physiol. |volume=270 |issue=3 Pt 1 |pages=G425–30 |year=1996 |pmid=8638708 |doi= |url=}}</ref><ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid7557131">{{cite journal |vauthors=Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada JR |title=Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon |journal=Gastroenterology |volume=109 |issue=5 |pages=1497–502 |year=1995 |pmid=7557131 |doi= |url=}}</ref><div style="text-align: center;">'''Flowchart showing pathogenesis of toxic megacolon'''<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref></div>
The following flowchart outlines the main [[Mechanism (biology)|mechanisms]] leading to the development of toxic megacolon, the explanation follows:<ref name="pmid8638708">{{cite journal |vauthors=Mourelle M, Vilaseca J, Guarner F, Salas A, Malagelada JR |title=Toxic dilatation of colon in a rat model of colitis is linked to an inducible form of nitric oxide synthase |journal=Am. J. Physiol. |volume=270 |issue=3 Pt 1 |pages=G425–30 |year=1996 |pmid=8638708 |doi= |url=}}</ref><ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid7557131">{{cite journal |vauthors=Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada JR |title=Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon |journal=Gastroenterology |volume=109 |issue=5 |pages=1497–502 |year=1995 |pmid=7557131 |doi= |url=}}</ref>
<br>
<br>
<div style="text-align: center;">'''Flowchart showing pathogenesis of toxic megacolon'''<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref></div>
<br>
<br>
{{familytree/start}}
{{familytree/start}}
{{familytree | | | | | | | | | A01 | | | | | |A01=Neutrophils}}
{{familytree | | | | | | | | | A01 | | | | | |A01=[[Neutrophils]]}}
{{familytree | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| }}
{{familytree | | |,|-|-|-|-|-|-|+|-|-|-|-|-|-|.| }}
{{familytree | | C01 | | | | | C02 | | | | | C03 |C01=Invade ulcerated mucosa|C02=Invade muscle layers|C03=Relase nitric oxide(NO)}}
{{familytree | | C01 | | | | | C02 | | | | | C03 |C01=Invade ulcerated mucosa|C02=Invade muscle layers|C03=Release [[nitric oxide(NO)]]}}
{{familytree | | |!| | | | | | |!| | | | | | |!| }}
{{familytree | | |!| | | | | | |!| | | | | | |!| }}
{{familytree | | D01 | | | | | D02 | | | | | D03 |D01=Cyrpt abcess and diffuse colitis|D02=Release cytokines, leukotriene B4 (LTB4), proteolytic enzymes|D03=Paralyses muscle cells }}  
{{familytree | | D01 | | | | | D02 | | | | | D03 |D01=[[Cyrpt abcess]] and diffuse [[colitis]]|D02=Release cytokines, leukotriene B4 (LTB4), proteolytic enzymes|D03=[[Paralysis]] muscle cells }}  
{{familytree | | | | | | |,|-|-|^|-|-|.| | | |!| }}
{{familytree | | | | | | |,|-|-|^|-|-|.| | | |!| }}
{{familytree | | | | | | E01 | | | | E02 | | E03 |E01=Directly damage muscle cells|E02=Systemic uptake of cytokines and other inflammatory mediators|E03=Dilation }}
{{familytree | | | | | | E01 | | | | E02 | | E03 |E01=Directly damage muscle cells|E02=Systemic uptake of cytokines and other inflammatory mediators|E03=[[Dilation]] }}
{{familytree | | | | | | |!| | | | | |!| | | |!| |}}
{{familytree | | | | | | |!| | | | | |!| | | |!| |}}
{{familytree | | | | | | |!| | |,|-| F01 | | |!| |F01=Fever, hypotension, tachycardia }}
{{familytree | | | | | | |!| | |,|-| F01 | | |!| |F01=[[Fever]], [[hypotension]], [[tachycardia]] }}
{{familytree | | | | | | |!| | |!| | | | | | |!| |}}
{{familytree | | | | | | |!| | |!| | | | | | |!| |}}
{{familytree | | | | | | |`|-| G01 |-|-|-|-|-|'| G01=Toxic megacolon}}
{{familytree | | | | | | |`|-| G01 |-|-|-|-|-|'| G01=Toxic megacolon}}
{{familytree/end}}
{{familytree/end}}
<br>
<br>'''Intestinal smooth muscle contractility'''
'''Role of smooth muscles'''
*There is a strong association between [[inflammatory]] conditions of the [[colon]] and decreased smooth muscle contractility.<ref name="pmid17598957">{{cite journal |vauthors=Ohama T, Hori M, Ozaki H |title=Mechanism of abnormal intestinal motility in inflammatory bowel disease: how smooth muscle contraction is reduced? |journal=J Smooth Muscle Res |volume=43 |issue=2 |pages=43–54 |year=2007 |pmid=17598957 |doi= |url=}}</ref><ref name="pmid22908862">{{cite journal |vauthors=Shea-Donohue T, Notari L, Sun R, Zhao A |title=Mechanisms of smooth muscle responses to inflammation |journal=Neurogastroenterol. Motil. |volume=24 |issue=9 |pages=802–11 |year=2012 |pmid=22908862 |pmc=4068333 |doi=10.1111/j.1365-2982.2012.01986.x |url=}}</ref>  
*There is a strong association between inflammatory conditions of the colon and decreased smooth muscle contractility.<ref name="pmid17598957">{{cite journal |vauthors=Ohama T, Hori M, Ozaki H |title=Mechanism of abnormal intestinal motility in inflammatory bowel disease: how smooth muscle contraction is reduced? |journal=J Smooth Muscle Res |volume=43 |issue=2 |pages=43–54 |year=2007 |pmid=17598957 |doi= |url=}}</ref><ref name="pmid22908862">{{cite journal |vauthors=Shea-Donohue T, Notari L, Sun R, Zhao A |title=Mechanisms of smooth muscle responses to inflammation |journal=Neurogastroenterol. Motil. |volume=24 |issue=9 |pages=802–11 |year=2012 |pmid=22908862 |pmc=4068333 |doi=10.1111/j.1365-2982.2012.01986.x |url=}}</ref>  
*The influx of [[calcium]] ([[Ca2+/calmodulin-dependent protein kinase|Ca2+]]) through voltage-dependent L-type Ca2+ channels plays a central role in the initiation of [[contraction]].<ref name="pmid22908862">{{cite journal |vauthors=Shea-Donohue T, Notari L, Sun R, Zhao A |title=Mechanisms of smooth muscle responses to inflammation |journal=Neurogastroenterol. Motil. |volume=24 |issue=9 |pages=802–11 |year=2012 |pmid=22908862 |pmc=4068333 |doi=10.1111/j.1365-2982.2012.01986.x |url=}}</ref>
*The influx of calcium (Ca2+) through voltage-dependent L-type Ca2+ channels plays a central role in the initiation of contraction.  
*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 [[filament]]<nowiki/>s 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]].<ref name="pmid2001831">{{cite journal |vauthors=Sethi AK, Sarna SK |title=Colonic motor activity in acute colitis in conscious dogs |journal=Gastroenterology |volume=100 |issue=4 |pages=954–63 |year=1991 |pmid=2001831 |doi= |url=}}</ref>
* These [[cytokines]] and [[chemokines]] may lead to alteration in the ionic [[concentration]] of the [[cells]] (which includes the [[concentration]] of [[calcium]] [[Ion|ions]]).<ref name="pmid150660192">{{cite journal |vauthors=Mawe GM, Collins SM, Shea-Donohue T |title=Changes in enteric neural circuitry and smooth muscle in the inflamed and infected gut |journal=Neurogastroenterol. Motil. |volume=16 Suppl 1 |issue= |pages=133–6 |year=2004 |pmid=15066019 |doi=10.1111/j.1743-3150.2004.00489.x |url=}}</ref>
* 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'''
'''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.<ref name="BassottiAntonelli2014">{{citejournal|last1=Bassotti|first1=Gabrio|last2=Antonelli|first2=Elisabetta|last3=Villanacci|first3=Vincenzo|last4=Baldoni|first4=Monia|last5=Dore|first5=Maria Pina|title=Colonic motility in ulcerative colitis|journal=United European Gastroenterology Journal|volume=2|issue=6|year=2014|pages=457–462|issn=2050-6406|doi=10.1177/2050640614548096}}</ref><ref name="GanBeck2003">{{cite journal|last1=Gan|first1=S. Ian|last2=Beck|first2=P. L.|title=A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management|journal=The American Journal of Gastroenterology|volume=98|issue=11|year=2003|pages=2363–2371|issn=0002-9270|doi=10.1111/j.1572-0241.2003.07696.x}}</ref><ref name="pmid5769743">{{cite journal |vauthors=Norland CC, Kirsner JB |title=Toxic dilatation of colon (toxic megacolon): etiology, treatment and prognosis in 42 patients |journal=Medicine (Baltimore) |volume=48 |issue=3 |pages=229–50 |year=1969 |pmid=5769743 |doi= |url=}}</ref><ref name="pmid12014723">{{cite journal |vauthors=Latella G, Vernia P, Viscido A, Frieri G, Cadau G, Cocco A, Cossu A, Tomei E, Caprilli R |title=GI distension in severe ulcerative colitis |journal=Am. J. Gastroenterol. |volume=97 |issue=5 |pages=1169–75 |year=2002 |pmid=12014723 |doi=10.1111/j.1572-0241.2002.05691.x |url=}}</ref>
*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]].<ref name="BassottiAntonelli2014">{{citejournal|last1=Bassotti|first1=Gabrio|last2=Antonelli|first2=Elisabetta|last3=Villanacci|first3=Vincenzo|last4=Baldoni|first4=Monia|last5=Dore|first5=Maria Pina|title=Colonic motility in ulcerative colitis|journal=United European Gastroenterology Journal|volume=2|issue=6|year=2014|pages=457–462|issn=2050-6406|doi=10.1177/2050640614548096}}</ref><ref name="GanBeck2003">{{cite journal|last1=Gan|first1=S. Ian|last2=Beck|first2=P. L.|title=A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management|journal=The American Journal of Gastroenterology|volume=98|issue=11|year=2003|pages=2363–2371|issn=0002-9270|doi=10.1111/j.1572-0241.2003.07696.x}}</ref><ref name="pmid5769743">{{cite journal |vauthors=Norland CC, Kirsner JB |title=Toxic dilatation of colon (toxic megacolon): etiology, treatment and prognosis in 42 patients |journal=Medicine (Baltimore) |volume=48 |issue=3 |pages=229–50 |year=1969 |pmid=5769743 |doi= |url=}}</ref><ref name="pmid12014723">{{cite journal |vauthors=Latella G, Vernia P, Viscido A, Frieri G, Cadau G, Cocco A, Cossu A, Tomei E, Caprilli R |title=GI distension in severe ulcerative colitis |journal=Am. J. Gastroenterol. |volume=97 |issue=5 |pages=1169–75 |year=2002 |pmid=12014723 |doi=10.1111/j.1572-0241.2002.05691.x |url=}}</ref>
'''Role of nitric oxide (NO)'''
'''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 nonadrenergic, noncholinergic neurotransmitter that induces colonic smooth muscle relaxation.<ref name="pmid12014723">{{cite journal |vauthors=Latella G, Vernia P, Viscido A, Frieri G, Cadau G, Cocco A, Cossu A, Tomei E, Caprilli R |title=GI distension in severe ulcerative colitis |journal=Am. J. Gastroenterol. |volume=97 |issue=5 |pages=1169–75 |year=2002 |pmid=12014723 |doi=10.1111/j.1572-0241.2002.05691.x |url=}}</ref><ref name="pmid8095033">{{cite journal |vauthors=Boeckxstaens GE, Pelckmans PA, Herman AG, Van Maercke YM |title=Involvement of nitric oxide in the inhibitory innervation of the human isolated colon |journal=Gastroenterology |volume=104 |issue=3 |pages=690–7 |year=1993 |pmid=8095033 |doi= |url=}}</ref><ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid7557131">{{cite journal |vauthors=Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada JR |title=Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon |journal=Gastroenterology |volume=109 |issue=5 |pages=1497–502 |year=1995 |pmid=7557131 |doi= |url=}}</ref><ref name="pmid11467676">{{cite journal |vauthors=Schwörer H, Bohn M, Waezsada SY, Raddatz D, Ramadori G |title=Successful treatment of megacolon associated with colitis with a nitric oxide synthase inhibitor |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=2273–4 |year=2001 |pmid=11467676 |doi=10.1111/j.1572-0241.2001.03986.x |url=}}</ref><ref name="GanBeck2003">{{cite journal|last1=Gan|first1=S. Ian|last2=Beck|first2=P. L.|title=A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management|journal=The American Journal of Gastroenterology|volume=98|issue=11|year=2003|pages=2363–2371|issn=0002-9270|doi=10.1111/j.1572-0241.2003.07696.x}}</ref>
*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.<ref name="pmid12014723">{{cite journal |vauthors=Latella G, Vernia P, Viscido A, Frieri G, Cadau G, Cocco A, Cossu A, Tomei E, Caprilli R |title=GI distension in severe ulcerative colitis |journal=Am. J. Gastroenterol. |volume=97 |issue=5 |pages=1169–75 |year=2002 |pmid=12014723 |doi=10.1111/j.1572-0241.2002.05691.x |url=}}</ref><ref name="pmid8095033">{{cite journal |vauthors=Boeckxstaens GE, Pelckmans PA, Herman AG, Van Maercke YM |title=Involvement of nitric oxide in the inhibitory innervation of the human isolated colon |journal=Gastroenterology |volume=104 |issue=3 |pages=690–7 |year=1993 |pmid=8095033 |doi= |url=}}</ref><ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid7557131">{{cite journal |vauthors=Mourelle M, Casellas F, Guarner F, Salas A, Riveros-Moreno V, Moncada S, Malagelada JR |title=Induction of nitric oxide synthase in colonic smooth muscle from patients with toxic megacolon |journal=Gastroenterology |volume=109 |issue=5 |pages=1497–502 |year=1995 |pmid=7557131 |doi= |url=}}</ref><ref name="pmid11467676">{{cite journal |vauthors=Schwörer H, Bohn M, Waezsada SY, Raddatz D, Ramadori G |title=Successful treatment of megacolon associated with colitis with a nitric oxide synthase inhibitor |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=2273–4 |year=2001 |pmid=11467676 |doi=10.1111/j.1572-0241.2001.03986.x |url=}}</ref><ref name="GanBeck2003">{{cite journal|last1=Gan|first1=S. Ian|last2=Beck|first2=P. L.|title=A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and management|journal=The American Journal of Gastroenterology|volume=98|issue=11|year=2003|pages=2363–2371|issn=0002-9270|doi=10.1111/j.1572-0241.2003.07696.x}}</ref>
'''Progression of toxic megacolon'''
'''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).<ref name="pmid7380218">{{cite journal |vauthors=Buckell NA, Williams GT, Bartram CI, Lennard-Jones JE |title=Depth of ulceration in acute colitis: correlation with outcome and clinical and radiologic features |journal=Gastroenterology |volume=79 |issue=1 |pages=19–25 |year=1980 |pmid=7380218 |doi= |url=}}</ref><ref name="pmid1246881">{{cite journal |vauthors=Rosenberg M |title=Toxic megacolon |journal=West. J. Med. |volume=124 |issue=2 |pages=122–7 |year=1976 |pmid=1246881 |pmc=1130453 |doi= |url=}}</ref><ref name="pmid2493427">{{cite journal |vauthors=Danovitch SH |title=Fulminant colitis and toxic megacolon |journal=Gastroenterol. Clin. North Am. |volume=18 |issue=1 |pages=73–82 |year=1989 |pmid=2493427 |doi= |url=}}</ref>
*The [[inflammatory]] process in toxic megacolon extends up to muscularis propria when compared to uncomplicated [[ulcerative colitis]] (limited to superfacial layer of [[submucosa]]).<ref name="pmid7380218">{{cite journal |vauthors=Buckell NA, Williams GT, Bartram CI, Lennard-Jones JE |title=Depth of ulceration in acute colitis: correlation with outcome and clinical and radiologic features |journal=Gastroenterology |volume=79 |issue=1 |pages=19–25 |year=1980 |pmid=7380218 |doi= |url=}}</ref><ref name="pmid1246881">{{cite journal |vauthors=Rosenberg M |title=Toxic megacolon |journal=West. J. Med. |volume=124 |issue=2 |pages=122–7 |year=1976 |pmid=1246881 |pmc=1130453 |doi= |url=}}</ref><ref name="pmid2493427">{{cite journal |vauthors=Danovitch SH |title=Fulminant colitis and toxic megacolon |journal=Gastroenterol. Clin. North Am. |volume=18 |issue=1 |pages=73–82 |year=1989 |pmid=2493427 |doi= |url=}}</ref>


*The depth of inflammation is known to correlate with the extent of colonic dilatation.<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid26411766">{{cite journal |vauthors=Akbarali HI, Kang M |title=Postranslational Modification of Ion Channels in Colonic Inflammation |journal=Curr Neuropharmacol |volume=13 |issue=2 |pages=234–8 |year=2015 |pmid=26411766 |pmc=4598435 |doi= |url=}}</ref><ref name="pmid24415856">{{cite journal |vauthors=Bassotti G, Antonelli E, Villanacci V, Salemme M, Coppola M, Annese V |title=Gastrointestinal motility disorders in inflammatory bowel diseases |journal=World J. Gastroenterol. |volume=20 |issue=1 |pages=37–44 |year=2014 |pmid=24415856 |pmc=3886030 |doi=10.3748/wjg.v20.i1.37 |url=}}</ref>
*The depth of [[inflammation]] is known to correlate with the extent of colonic [[Dilation|dilatation]].<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref><ref name="pmid26411766">{{cite journal |vauthors=Akbarali HI, Kang M |title=Postranslational Modification of Ion Channels in Colonic Inflammation |journal=Curr Neuropharmacol |volume=13 |issue=2 |pages=234–8 |year=2015 |pmid=26411766 |pmc=4598435 |doi= |url=}}</ref><ref name="pmid24415856">{{cite journal |vauthors=Bassotti G, Antonelli E, Villanacci V, Salemme M, Coppola M, Annese V |title=Gastrointestinal motility disorders in inflammatory bowel diseases |journal=World J. Gastroenterol. |volume=20 |issue=1 |pages=37–44 |year=2014 |pmid=24415856 |pmc=3886030 |doi=10.3748/wjg.v20.i1.37 |url=}}</ref>


==Associated Conditions==
==Associated Conditions==
Line 42: Line 52:
**[[Ulcerative colitis]]
**[[Ulcerative colitis]]
**[[Crohn's disease]]
**[[Crohn's disease]]
*''Clostridium difficile'' pseudomembranous enterocolitis
*''[[Clostridium difficile]]'' [[pseudomembranous enterocolitis]]
*[[Ischemia entrocolitis]]
*Ischemia enterocolitis
*[[Methotrexate therapy]]
*[[Methotrexate]] therapy
*[[Colon cancer]]
*[[Colon cancer]]


==Gross Pathology==
==Gross Pathology==
*Gross pathology of toxic megacolon include:<ref name="pmid1467905">{{cite journal |vauthors=Kobayasi S, Mendes EF, Rodrigues MA, Franco MF |title=Toxic dilatation of the colon in Chagas' disease |journal=Br J Surg |volume=79 |issue=11 |pages=1202–3 |year=1992 |pmid=1467905 |doi= |url=}}</ref><ref name="pmid24294121">{{cite journal |vauthors=Seltman AK |title=Surgical Management of Clostridium difficile Colitis |journal=Clin Colon Rectal Surg |volume=25 |issue=4 |pages=204–9 |year=2012 |pmid=24294121 |pmc=3577611 |doi=10.1055/s-0032-1329390 |url=}}</ref>
*Gross pathology of toxic megacolon include:<ref name="pmid1467905">{{cite journal |vauthors=Kobayasi S, Mendes EF, Rodrigues MA, Franco MF |title=Toxic dilatation of the colon in Chagas' disease |journal=Br J Surg |volume=79 |issue=11 |pages=1202–3 |year=1992 |pmid=1467905 |doi= |url=}}</ref><ref name="pmid24294121">{{cite journal |vauthors=Seltman AK |title=Surgical Management of Clostridium difficile Colitis |journal=Clin Colon Rectal Surg |volume=25 |issue=4 |pages=204–9 |year=2012 |pmid=24294121 |pmc=3577611 |doi=10.1055/s-0032-1329390 |url=}}</ref>
**Dilated colon
**Dilated [[colon]]
**Eroded mucosa
**Eroded [[mucosa]]
**Diffuse ulcerations
**Diffuse [[ulcerations]]
**Raised mucosal nodules
**Raised mucosal [[nodules]]
**Yellowish-white superficial plaques with normal intervening mucosa (typical pseudomembrane appearance)   
**Yellowish-white [[superficial]] [[plaques]] with normal intervening mucosa (typical pseudomembrane appearance)   
**Extensive denudation
**Extensive denudation
[[image:Toxic megacolon 1.JPG|400px|thumb|left|Gross pathology of toxic megacolon 1 [https://commons.wikimedia.org/wiki/File:Toxic_megacolon_1.JPG Source:Wikimedia commons]]]
[[image:Toxic megacolon 1.JPG|300px|thumb|left|Gross pathology of toxic megacolon 1 [https://commons.wikimedia.org/wiki/File:Toxic_megacolon_1.JPG Source:By Donated by the pathologist at work. (Dr. Rocke Robertson) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], Wikimedia commons]]]
[[image:Toxic megacolon 2.JPG|400px|thumb|left|Gross pathology of toxic megacolon 2 [https://commons.wikimedia.org/wiki/File:Toxic_megacolon_2.JPG Source:Wikimedia commons]]]
[[image:Toxic megacolon 2.JPG|300px|thumb|left|Gross pathology of toxic megacolon 2 [https://commons.wikimedia.org/wiki/File:Toxic_megacolon_2.JPG Source:By Donated by the pathologist at work. (Dr. Rocke Robertson) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)], Wikimedia commons]]]
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==Microscopic Pathology==
==Microscopic Pathology==
*Microscopic histopathological analysis include:<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref>
*Microscopic [[histopathological]] analysis include:<ref name="pmid9482465">{{cite journal |vauthors=Sheth SG, LaMont JT |title=Toxic megacolon |journal=Lancet |volume=351 |issue=9101 |pages=509–13 |year=1998 |pmid=9482465 |doi=10.1016/S0140-6736(97)10475-5 |url=}}</ref>
**Transmural acute inflammation of colon
**Transmural acute inflammation of [[colon]]
**Necrosis
**[[Necrosis]]
**Replacement by granulation tissue infiltrated by histiocytes, neutrophils, lymphocytes, and plasma cells
**Replacement by granulation tissue infiltrated by [[histiocytes]], [[neutrophils]], [[lymphocytes]], and [[plasma cells]]
**Shortened and rounded muscle with aggregates of eosinophilic cytoplasm
**Shortened and rounded muscle with aggregates of [[eosinophilic]] [[cytoplasm]]
**Preserved colonic submucosal and myenteric plexuses
**Preserved colonic [[submucosal]] and myenteric [[plexuses]]


==References==
==References==
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Latest revision as of 21:50, 1 April 2019

Toxic Megacolon Microchapters

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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

Role of smooth muscles in inflammatory conditions

Smooth muscle contraction in toxic megacolon

Role of nitric oxide (NO)

Progression of toxic megacolon

Associated Conditions

Conditions associated with toxic megacolon include:[19][20][21][22][23]

Gross Pathology

Gross pathology of toxic megacolon 1 Source:By Donated by the pathologist at work. (Dr. Rocke Robertson) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0), Wikimedia commons]
Gross pathology of toxic megacolon 2 Source:By Donated by the pathologist at work. (Dr. Rocke Robertson) [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0), Wikimedia commons]


Microscopic Pathology

References

  1. ↑ 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. ↑ 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. ↑ 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.
  4. ↑ 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. ↑ 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.
  6. ↑ Sethi AK, Sarna SK (1991). "Colonic motor activity in acute colitis in conscious dogs". Gastroenterology. 100 (4): 954–63. PMID 2001831.
  7. ↑ 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.
  8. ↑ Template:Citejournal
  9. ↑ 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.
  10. ↑ 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. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ Rosenberg M (1976). "Toxic megacolon". West. J. Med. 124 (2): 122–7. PMC 1130453. PMID 1246881.
  16. ↑ Danovitch SH (1989). "Fulminant colitis and toxic megacolon". Gastroenterol. Clin. North Am. 18 (1): 73–82. PMID 2493427.
  17. ↑ Akbarali HI, Kang M (2015). "Postranslational Modification of Ion Channels in Colonic Inflammation". Curr Neuropharmacol. 13 (2): 234–8. PMC 4598435. PMID 26411766.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Autenrieth DM, Baumgart DC (2012). "Toxic megacolon". Inflamm. Bowel Dis. 18 (3): 584–91. doi:10.1002/ibd.21847. PMID 22009735.
  21. ↑ Autenrieth, Daniel M.; Baumgart, Daniel C. (2012). "Toxic megacolon". Inflammatory Bowel Diseases. 18 (3): 584–591. doi:10.1002/ibd.21847. ISSN 1078-0998.
  22. ↑ SILVERBERG D, ROGERS AG (1964). "TOXIC MEGACOLON IN ULCERATIVE COLITIS". Can Med Assoc J. 90: 357–63. PMC 1922240. PMID 14122466.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.

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