Introduction

As its name suggests, toxic megacolon is a bowel disease consisting of two elements - dilatation of the large intestine (colon), in the absence of a cause of bowel obstruction and “toxicity” (the presence of sepsis). These conditions are more precisely defined, with toxic megacolon being suspected when the horizontally located middle section of the large bowel (the transverse colon) is dilated to a greater or equal to 6 cm in diameter (as seen on images from abdominal x-rays or CT scans). Signs of toxicity (sepsis) are the physical signs of a fever (usually greater than 38 degrees C), a rapid pulse rate, a raised white blood cell count, and frequently the presence of anaemia (low red blood cells) accompanied by dehydration, mental changes such as drowsiness or confusion, low blood pressure and abnormalities in blood electrolyte (blood salts) levels.¹

Clinically, toxic megacolon presents with symptoms of abdominal pain, swelling of the abdomen, vomiting, diarrhoea (with or without the presence of blood) and specific features relating to the underlying cause. Therefore, a knowledge of the various conditions that can result in toxic megacolon is important in informing diagnosis and treatment.^1,2 

Although there are other conditions in which the large bowel is found to be dilated, distinguishing cases of toxic megacolon is particularly important because of the high risk of bowel perforation, leading to peritonitis (inflammation of the abdominal cavity lining), which carries a high risk of mortality and the high risk of death from the toxic (septic) element of the disease. Other potentially fatal complications include haemorrhage (bleeding from the bowel), the formation of abscesses within the abdominal cavity and abdominal compartment syndrome (a condition where fluid builds up in the abdomen to the extent that the pressure causes dysfunction of the internal organs).³

Broadly speaking, the causes of toxic megacolon can be divided into those precipitated by non-infective causes of bowel inflammation (inflammatory causes) and those related to an infectious agent (infectious causes). 

Inflammatory Causes

48% of all cases of toxic megacolon are related to inflammatory bowel disease, namely Crohn's disease and ulcerative colitis. Studies of the incidence of toxic megacolon in the two conditions have produced conflicting results, with some studies showing higher incidences in ulcerative colitis compared to Crohn’s disease and vice versa.³ The overall incidence of toxic megacolon in both forms of inflammatory bowel disease is estimated to be between 1-5%. Whilst Crohn's disease and ulcerative colitis account for the vast majority of inflammatory causes, theoretically, any disease causing widespread inflammation of the large bowel can lead to toxic megacolon. A number of rarer inflammatory causes are listed in this article.²

Crohn's Disease

Crohn’s disease is an inflammatory (caused by the body’s immune system attacking itself) bowel disease affecting around 10.6 in every 100,000 people in the UK.⁴ Crohn’s disease is characterised by recurrent episodes of inflammation of the gastrointestinal tract. Unlike ulcerative colitis which is confined to the large bowel (colon and rectum), Crohn's disease can affect any part of the gastrointestinal tract - from the mouth to the anus. In most patients however the disease primarily affects the colon and the ileal section of the small intestine. About ⅓ of patients have disease just affecting the ileum, ⅓ just affecting the colon and ⅓ with, disease affecting both.

Recurrent episodes of inflammation are characterised by diarrhoea, abdominal pain, rectal bleeding (more common in ulcerative colitis), frequently lesions around the anus such as hemorrhoids and anal fissures and less commonly symptoms from the upper gastrointestinal tract such as vomiting and difficulty swallowing. Additionally these episodes are accompanied by general symptoms of weight loss, loss of appetite, generally feeling unwell (malaise) and "low grade fevers". Camera examination of the bowel (endoscopy) reveals the typical inflammatory ulcers found in the bowel in Crohn’s disease - so-called “skip-lesions” as they appear as ulcers interspersed with healthy patches of gut lining. The ulcers are said to have a “cobblestone” appearance to their surface.⁵

Crohn’s disease does not usually cause continuous inflammation of the entire large bowel and rarely affects the rectum, distinguishing it from ulcerative colitis. Toxic megacolon is more likely in the earlier stages of Crohn’s disease as after the disease progresses, scar tissue which forms to heal the ulcerations causes the bowel to become stiff and less likely to dilate. Toxic megacolon also only occurs in Crohn’s disease when the colon is affected. The use of medications which suppress the immune system (such as corticosteroids) to treat both Crohn’s and ulcerative colitis may mask the signs of sepsis in the early stages of toxic megacolon.^5,3

Ulcerative Colitis

Ulcerative colitis is more common in adults than Crohn’s disease (although the reverse is the case in children), with a prevalence of 156-291 cases in every 100,000 people. Like Crohn’s disease, ulcerative colitis arises from a disordered immune response, in which the immune system attacks the gastrointestinal tract. Ulcerative colitis can affect any part of the large bowel with inflammation of the rectum (proctitis) being the most common, followed by disease affecting the left side of the colon with inflammation of the entire colon (pancolitis) occurring in 14-35% of patients. Toxic megacolon most commonly occurs in the presence of pancolitis (inflammation of the entire colon) and still represents the most common fatal complication of ulcerative colitis.^1,6,10

The typical symptoms of ulcerative colitis are episodic bouts of bloody diarrhoea, frequently with mucus present. Tenesmus (pain in the rectum) and urgency to empty the bowels are also frequent symptoms. Similar to Crohn’s disease, generalised symptoms of weight loss, malaise and loss of appetite may accompany the episodes. Because the symptoms of some infections causing inflammation of the gut are clinically indistinguishable from ulcerative colitis, it is important to exclude an infective cause when making the diagnosis. Diagnosis is aided by endoscopic examination of the large bowel (either procto-sigmoidoscopy or colonoscopy) revealing the typical features of a fragile, friable gut surface lining, a granular appearance and the presence of erosions of the gut lining with areas between the erosions appearing raised (pseudopolyposis).⁶

Rarer inflammatory causes

Aside from Crohn’s disease and ulcerative colitis, other conditions leading to inflammation of the bowel in the absence of an infective cause may also result in the development of toxic megacolon, although far more rarely. These include:^1,7

• Neutropenic colitis
• Ischaemic colitis
• Radiation-induced colitis
• Colonic lymphoma
• Karposi’s sarcoma
• Pseudomembranous colitis secondary to methotrexate treatment
• Gastro-intestinal graft vs host disease
• Obstructive Colon cancer

Infective Causes

Whilst the incidence of toxic megacolon due to inflammatory bowel disease appears to be falling - possibly due to improved awareness and monitoring and recent advances in medical treatment of inflammatory bowel disease, toxic megacolon due to infective causes is increasing, chiefly because of the rise in cases of Clostridium difficile (also known as Clostridioides difficile) infection. Aside from infection with the clostridium difficile bacteria, a number of other infective agents - bacterial, fungal and viral and parasitic have been associated with toxic megacolon.^2,8

Clostridium Difficile

Clostridium difficile is a bacterium which causes an infection characterised by diarrhoea which can progress to toxic megacolon in as many as 4.3% of all cases of infection. There has been a significant rise in cases of C.difficile infection in recent years in Western countries, with incidences estimated to be as high as 631.8 cases per 100,000 population. C.difficile forms particularly hardy spores which can be resistant to common disinfectants, making spread is particularly prevalent in institutions and hospitals.^3,8

The main factors however responsible for the rise in cases are an increasingly aged population in the Western world (incidence increases with advancing age) and the extensive use of antibiotics. Antibiotics used for other illnesses promote infection with C.difficile by altering the gut microbiome by killing off the “good bacteria”, allowing damaging bacteria such as C.difficile to thrive in their place. Risk factors for contracting C. difficile include diabetes, heart disease, advancing age, female sex, being on PPI drugs (such as omeprazole) for heartburn or stomach ulcers, corticosteroid drugs and being hospitalised or in long term care. Whilst C.difficile does respond to antibiotic treatments such as vancomycin, antibiotic resistance is developing and re-infection rates are as high as 15-35%.⁸

Long term strategies to reduce C.difficile infection are around “antibiotic stewardship”, processes designed to prevent the over-prescription of inappropriate antibiotics and improving hygiene in hospitals and care facilities. Cases of toxic megacolon related to C.difficile generally respond less well to medical treatment than other causes and frequently, require surgical intervention. C.difficile infection is more common in patients with inflammatory bowel disease due to a combination of frequent hospitalisations, altered gut microbiome, long term use of immuno-suppressive drugs and frequent antibiotic prescriptions.⁸

Other bacterial infective agents causing toxic megacolon

Other bacteria which cause generalised inflammation of the majority of the large bowel (pancolitis) have also been linked to the development of toxic megacolon. These are primarily:

• Salmonella (the cause of Salmonella food poisoning, commonly found in undercooked eggs and poultry)
• Shigella (the cause of bacterial dysentery)
• Yersinia (the cause of yersiniosis, a form of food poisoning mainly transmitted through undercooked pork) 
• Enterohemorrhagic strains of E.Coli (E.Coli 0157)^3,7

Other organisms causing toxic megacolon

Parasites, fungi and viruses are also linked to the development of toxic megacolon, however aside from the cytomegalovirus (CMV)  virus, which deserves special mention as it is the most common cause of toxic megacolon in HIV and AIDS patients, they are generally rare causes.

Parasites causing toxic megacolon

• Entamoeba histolytica (causes amoebic colitis through infected food/water, usually there will be a history of travel to an endemic area)³
• Cryptosporidium (more common in children aged 1-5, those working with livestock, or in contaminated water supplies)³

Fungi causing toxic megacolon

• Rarely caused by Aspergillus³

Viruses causing toxic megacolon

The cytomegalovirus (CMV) is an important cause of toxic megacolon in patients with HIV and AIDS. Also, in patients with inflammatory bowel disease, particularly ulcerative colitis who may be on immunosuppressive drugs to control bowel inflammation, CMV infection is more common, thought to present a “double hit” in terms of toxic megacolon risk, along with the inflammatory bowel disease itself. As with "C.difficile colitis induced toxic megacolon", cases with CMV colitis respond poorly to medical treatment and require surgery more frequently. Patients with advanced AIDS however may not be suitable candidates for major surgery and will often require treatment in the intensive care unit and careful medical decompression.^1,7

Precipitating factors in the development of toxic megacolon

In addition to the causative factors discussed, there are a number of medical treatments or conditions which may precipitate or increase the risk of developing toxic megacolon in the presence of a causative risk factor (such as inflammatory bowel disease).These include:²

• Low potassium levels (hypokalaemia) - makes the gut less mobile
• Barium enema procedure to image the bowel
• Colonoscopy procedure (camera examination of the bowel)
• Certain medications - anti-motility agents used in diarrhoea and irritable bowel disorder(IBS), opioid pain-killers, certain antidepressants, anticholinergic drugs

Shared pathological mechanisms in both infective and inflammatory causes of toxic megacolon

Regardless, the pathological processes involved in the development of toxic megacolon are probably broadly similar. Immune cells (such as neutrophils) invade the gut lining, where they lead to inflammation of the surface (mucosal) layer. In toxic megacolon, they also appear to invade the muscle layer of the gut, where they are responsible for the release of inflammatory chemicals into the muscle layer; these include cytokines and leukotrienes and enzymes that digest proteins. Neutrophils and other inflammatory cells also release nitric oxide, which is toxic to bacteria but also acts as a transmitter which relaxes smooth muscle cells. It is believed that the release of nitric oxide combined with damage to the muscle layer leads to the dilatation of the bowel occurring in toxic megacolon. Meanwhile, the inflammatory chemicals released such as cytokines and leukotriene B4 enter the bloodstream and cause the systemic effects of toxicity like fever, low blood pressure and rapid pulse. Experimental studies of bowel removed from patients with toxic megacolon have shown increased levels of nitric oxide synthase, the enzyme that produces nitric oxide.^9,10 

Summary

Toxic megacolon is a relatively rare condition characterised by a dilated bowel and generalised signs of sepsis. If not appropriately treated the condition can be fatal due to complications of sepsis, bowel perforation or peritonitis. Approximately half of all cases are related to inflammatory bowel disease (Crohn’s disease and ulcerative colitis) with a few other rarer inflammatory causes. The remainder of cases are related to infections, chiefly with the clostridium difficile bacterium, cases of which are steadily rising in the Western world due to an increasingly aging population and the overuse of broad spectrum antibiotics. Other infections such as salmonella and shigella (dysentery) are also implicated. Infection with the CMV virus in patients with HIV and inflammatory bowel disease whilst relatively uncommon is an important cause in these patient groups. A few other pathogens are rarely implicated including fungi and parasites. Irrespective of the cause, it appears there are common pathological processes in infective and inflammatory aetiologies in which the role of nitric oxide is central.