Toxic megacolon

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

Toxic megacolon was first discovered by Marshak and Lester in 1950. Jalen criteria was developed by Jalen et al to diagnose toxic megacolon in 1969. 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. The most common cause of toxic megacolon include inflammatory bowel disease and Clostridium difficile pseudomembranous colitis. The most common cause of toxic megacolon include inflammatory bowel disease and Clostridium difficile pseudomembranous colitis. The precise incidence of toxic megacolon is unknown in general population. The incidence of toxic megacolon in the associated disorders including ulcerative colitis and Crohn’s disease is 1000-2500 in 100,000 cases and 4400-6300 in 100,000 cases, respectively. The mortality rate of toxic megacolon associated with Clostridium difficile is approximately 38%-80%. Common risk factors in the development of toxic negacolon include discontinuation of steroids, use of barium enemas, colonoscopy, chemotherapy, antidiarrheal drugs, anticholinergic drugs, narcotics, Severe chronic obstructive pulmonary disease, organ transplantation, cardiothoracic procedures, diabetes mellitus, immunosuppression, renal failure. If left untreated, toxic megacolon in patients with ulcerative colitis lead to death in 0.2% patients. Common complications of toxic megacolon include perforation, bleeding, shock, sepsis. Prognosis is generally good. The diagnostic criteria for toxic megacolon is Jalan diagnostic criteria. Common symptoms of toxic megacolon include abdominal pain and cramping, diarrhea and fever. Less common symptoms include constipation and disorientation.Patients with toxic megacolon usually appear ill. Physical examination of patients with toxic megacolon is usually remarkable for abdominal pain, rebound tenderness and guarding, hypotension and tachycardia. Laboratory findings consistent with the diagnosis of toxic megacolon include anemia and leukocytosis. Some patients with toxic megacolon may have elevated concentration of Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) , which is usually suggestive of inflammation. An x-ray may be helpful in the diagnosis of toxic megacolon. Findings on an x-ray diagnostic of toxic megacolon include dilated transverse colon (>6cm), thumbprinting, free intraperitoneal air and intraluminal soft-tissue masses. Ultrasound may be helpful in the diagnosis of toxic megacolon. Findings on an ultrasound suggestive of toxic megacolon include loss of haustra coli of the colon, hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon and significant dilation of the transverse colon. Abdominal CT scan may be helpful in the diagnosis of toxic megacolon. Findings on CT scan diagnostic of toxic megacolon include dilated transverse colon, loss of colonic haustrations, segmental parietal thinning,Intraluminal soft-tissue masses. Medical therapy of toxic megacolon include stablizing the patient, decompression and medications. Medications for toxic megacolon include corticosteroids, immunosuppresants and antibiotics. The mainstay of treatment for toxic megacolon is medical therapy. Surgery is usually reserved for patients with either failed medical therapy, progressive toxicity or dilation and signs of perforation. There are no established measures for the prevention of toxic megacolon.

Toxic megacolon was first discovered by Marshak and Lester in 1950. Jalen criteria was developed by Jalen et al to diagnose toxic megacolon in 1969.

There is no established system for the classification of toxic megacolon.

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.

The most common cause of toxic megacolon include inflammatory bowel disease and Clostridium difficile pseudomembranous colitis.

The precise incidence of toxic megacolon is unknown in general population. The incidence of toxic megacolon in the associated disorders including ulcerative colitis and Crohn’s disease is 1000-2500 in 100,000 cases and 4400-6300 in 100,000 cases, respectively. The mortality rate of toxic megacolon associated with Clostridium difficile is approximately 38%-80%.

Common risk factors in the development of toxic negacolon include discontinuation of steroids, use of barium enemas, colonoscopy, chemotherapy, antidiarrheal drugs, anticholinergic drugs, narcotics, Severe chronic obstructive pulmonary disease, organ transplantation, cardiothoracic procedures, diabetes mellitus, immunosuppression, renal failure.

There is insufficient evidence to recommend routine screening for toxic megacolon.

If left untreated, toxic megacolon in patients with ulcerative colitis lead to death in 0.2% patients. Common complications of toxic megacolon include perforation, bleeding, shock, sepsis. Prognosis is generally good.

The diagnostic criteria for toxic megacolon is Jalan diagnostic criteria. It is based on clinical findings, physical exam signs and lab findings.

Common symptoms of toxic megacolon include abdominal pain and cramping, diarrhea and fever. Less common symptoms include constipation and disorientation.

Patients with toxic megacolon usually appear ill. Physical examination of patients with toxic megacolon is usually remarkable for abdominal pain, rebound tenderness and guarding, hypotension and tachycardia.

Laboratory findings consistent with the diagnosis of toxic megacolon include anemia and leukocytosis. Some patients with toxic megacolon may have elevated concentration of Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) , which is usually suggestive of inflammation.

An ECG may be helpful in the diagnosis of toxic megacolon. Findings on an ECG suggestive of toxic megacolon include sinus tachycardia.

An x-ray may be helpful in the diagnosis of toxic megacolon. Findings on an x-ray diagnostic of toxic megacolon include dilated transverse colon (>6cm), thumbprinting, free intraperitoneal air and intraluminal soft-tissue masses.

Ultrasound may be helpful in the diagnosis of toxic megacolon. Findings on an ultrasound suggestive of toxic megacolon include loss of haustra coli of the colon, hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon and significant dilation of the transverse colon.

Abdominal CT scan may be helpful in the diagnosis of toxic megacolon. Findings on CT scan diagnostic of toxic megacolon include dilated transverse colon, loss of colonic haustrations, segmental parietal thinning,Intraluminal soft-tissue masses.

There are no MRI findings associated with toxic megacolon.

There are no other imaging findings associated with toxic megacolon.

There are no other diagnostic studies associated with toxic megacolon.

Medical therapy of toxic megacolon include stablizing the patient, decompression and medications. Medications for toxic megacolon include corticosteroids, immunosuppresants and antibiotics.

The mainstay of treatment for toxic megacolon is medical therapy. Surgery is usually reserved for patients with either failed medical therapy, progressive toxicity or dilation and signs of perforation.

There are no established measures for the primary prevention of toxic megacolon.

There are no established measures for the secondary prevention of toxic megacolon.

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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]

Toxic megacolon was first discovered by Marshak and Lester in 1950. Jalen criteria was developed by Jalen et al to diagnose toxic megacolon in 1969. Jalen criteria was developed by Jalen et al to diagnose toxic megacolon in 1969.

• Toxic megacolon was first discovered by Marshak and Lester in 1950.^[1]
• In 1950, Marshak was the first to discover the association between Clostridium difficile and the development of toxic megacolon.^[2]

• Jalen criteria was developed by Jalen et al to diagnose toxic megacolon in 1969.^[3][4]

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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]

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.

The following flowchart outlines the main mechanisms leading to the development of toxic megacolon, the explanation follows:^[1][2][3]

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]

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

• Inflammatory bowel disease
  • Ulcerative colitis
  • Crohn’s disease
• Clostridium difficile pseudomembranous enterocolitis
• Ischemia enterocolitis
• Methotrexate therapy
• Colon cancer

• 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 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

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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]

The most common cause of toxic megacolon include inflammatory bowel disease and Clostridium difficile pseudomembranous colitis.

• There are no life-threatening causes of toxic megacolon.

Common causes of toxic megacolon include:^{[1][2][3][4][5][6][7]}

• Inflammatory
  • Ulcerative colitis
  • Crohn disease
  • Behçet disease
  • Bacterial
    • Clostridium difficile
    • Salmonella Typhoid and non-thyphoid
    • Shigella
    • Yersinia
    • Campylobacter
    • Escherichia coli
  • Viral
    • Cytomegalovirus (CMV)
    • Rotavirus
  • Parasitic
    • Entamoeba
    • Cryptosporidium
• Ischemic colitis
• Kaposi sarcoma

Less common causes of toxic megacolon include:^{[8][9][10][11][12]}

• Aspergillosis
• Collagenous colitis
• Rotavirus
• Malignancy like colonic lymohoma
• Pseudomembranous colitis secondary to methotrexate therapy
• Nonspecific colitis secondary to chemotherapy
• Cessation or interruption of ulcerative colitis therapy (5-ASA agents or steroids)
• Radition colitis

Cardiovascular	No underlying causes
Chemical/Poisoning	No underlying causes
Dental	No underlying causes
Dermatologic	No underlying causes
Drug Side Effect	No underlying causes
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	Ulcerative colitis, Crohn’s disease, collagenous colitis
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Bacterial, Clostridium difficile, Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli, Cytomegalovirus (CMV), Rotavirus, Entamoeba, Cryptosporidium
Musculoskeletal/Orthopedic	No underlying causes
Neurologic	No underlying causes
Nutritional/Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Kaposi sarcoma
Ophthalmologic	No underlying causes
Overdose/Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal/Electrolyte	No underlying causes
Rheumatology/Immunology/Allergy	Behçet disease
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

List the causes of the disease in alphabetical order.

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• Toxic megacolon must be differentiated from other diseases that cause abdominal pain, fever,diarrhea such as acute appendicitis, acute diverticulitis, inflammatory bowel disease, whipple’s disease, tropical sprue, infective colitis, viral hepatitis (hepatitis A and hepatitis E), liver abscess, spontaneous bacterial peritonitis, mesenteric ischemia, and acute ischemic colitis.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram

Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Toxic megacolon Diffuse + − − − − + − − + ± + Hypoactive Anemia Leukocytosis especially in patients with Clostridium difficile infection Hypoalbuminemia Metabolic alkalosis associated with a poor prognosis Metabolic acidosis secondary to ischemic colitis CT and Ultrasound shows: Loss of colonic haustration Hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon Prominent dilation of the transverse colon (>6 cm) Insignificant dilation of ileal bowel loops (diameter >18 mm) with increased intraluminal gas and fluid Acute appendicitis Starts in epigastrium, migrates to RLQ + Positive in pyogenic appendicitis + − − ± − − Positive in perforated appendicitis + + Hypoactive Leukocytosis Ct scan Ultrasound Positive Rovsing sign Positive Obturator sign Positive Iliopsoas sign Acute diverticulitis LLQ + ± + − + ± − + Positive in perforated diverticulitis + + Hypoactive Leukocytosis CT scan Ultrasound History of constipation Inflammatory bowel disease Diffuse ± − − ± − + + + − − − Normal or hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease String sign on abdominal x-ray in Crohn’s disease Extra intestinal findings: Uveitis Arthritis Whipple’s disease Diffuse ± − − ± − + + − ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Tropical sprue Diffuse + − − − − + + − − − − N Fat soluble vitamin deficiency Hypoalbuminemia Fecal stool test Barium studies: Dilation and edema of mucosal folds Steatorrhea– 10-40 g/day (Normal=5 g/day) Infective colitis Diffuse + − ± − − + − + Positive in fulminant colitis ± ± Hyperactive Stool culture and studies Shiga toxin in bloody diarrhea PCR CT scan Bowel wall thickening Edema Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Viral hepatitis RUQ + − + + − Positive in Hep A and E + − Positive in fulminant hepatitis Positive in acute + N Abnormal LFTs Viral serology US Hep A and E have fecal-oral route of transmission Hep B and C transmits via blood transfusion and sexual contact. Liver abscess RUQ + + + + − ± + − + + ± Normal or hypoactive CBC Blood cultures Abnormal liver function tests US CT Spontaneous bacterial peritonitis Diffuse + − − Positive in cirrhotic patients − + − − ± + + Hypoactive Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism Ultrasound for evaluation of liver cirrhosis Mesenteric ischemia Periumbilical Positive if bowel becomes gangrenous − + − − + + + Positive if bowel becomes gangrenous Positive if bowel becomes gangrenous − Hyperactive to absent Leukocytosis and lactic acidosis Amylase levels D-dimer CT angiography SMA or SMV thrombosis Also known as abdominal angina that worsens with eating Acute ischemic colitis Diffuse + ± + − − + + + + + + Hyperactive then absent Leukocytosis Abdominal x-ray Distension and pneumatosis CT scan Double halo appearance, thumbprinting Thickening of bowel May lead to shock

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Farima Kahe M.D. [2]

The precise incidence of toxic megacolon is unknown in general population. The incidence of toxic megacolon in the associated disorders including ulcerative colitis and Crohn’s disease is 1000-2500 in 100,000 cases and 4400-6300 in 100,000 cases, respectively. The mortality rate of toxic megacolon associated with Clostridium difficile is approximately 38%-80%.

• The precise incidence of toxic megacolon is unknown in general population. The incidence of toxic megacolon in the associated disorders including ulcerative colitis, Crohn’s disease and Clostridium difficile is:^[1][2][3]
  • 1000-2500 in 100,000 cases of the ulcerative colitis.
  • 4400-6300 in 100,000 cases of the Crohn’s disease.
  • 400-3000 in 100,000 cases of the Clostridium difficile.

• The mortality rate of toxic megacolon associated with clostridium difficile is approximately 38%-80%.^[4][5]

• Patients of all age groups may develop toxic megacolon.^[6]

• There is no racial predilection described in toxic megacolon.^[7]

• Toxic megacolon affects men and women equally.^[8]

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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]

Common risk factors in the development of toxic negacolon include discontinuation of steroids, use of barium enemas, colonoscopy, chemotherapy, antidiarrheal drugs, anticholinergic drugs, narcotics, Severe chronic obstructive pulmonary disease, organ transplantation, cardiothoracic procedures, diabetes mellitus, immunosuppression, renal failure.

• Common risk factors in the development of toxic megacolon include use of barium enema, colonoscopy, chemotherapy, antidiarrheal drugs, anticholinergic drug, narcotics, diabetes mellitus and immunosuppression.
• Common risk factors in the development of toxic megacolon include:^{[1][2][3][4][5]}
  • Use of barium enema
  • Colonoscopy
  • Chemotherapy
  • Antidiarrheal drugs
  • Anticholinergic drug
  • Narcotics
  • Diabetes mellitus
  • Immunosuppression

• Less common risk factors in the development of toxic megacolon include:^[6][7]
  • Organ transplantation
  • Discontinuation of steroids
  • Severe chronic obstructive pulmonary disease
  • Renal failure
  • Cardio-thoracic procedures

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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]

If left untreated, toxic megacolon in patients with ulcerative colitis lead to death in 0.2% patients. Common complications of toxic megacolon include perforation, bleeding, shock, sepsis. Prognosis is generally good.

• If left untreated, toxic megacolon in patients with ulcerative colitis lead to death in 0.2% patients.^[1]
• The following factors are associated with increased mortality:^[2][3]
  • Age > 40 years
  • Female gender
  • Lower albumin level
  • Lower serum CO2
  • High BUN
• The duration of inflammatory bowel disease do not affect mortality.^[4][5]
• There is recurrence rate of approximately 29% for patients of either toxic megacolon or fulminant colitis.^[6]

• Common complications of toxic megacolon include:^[3][7]
  • Perforation or opening in the wall of the colon
  • Bleeding
  • Shock
  • Sepsis

• Depending on the presence of the perforation at the time of diagnosis, the prognosis may vary. However, the prognosis is generally regarded as excellent without perforation.^[5][8]
• Early surgical management leads to better prognosis when compared to medical management.^[6][9]
• Majority of patients of toxic megacolon treated with medical management requires colectomy on long term follow up.^[2][10]

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