COLITIS
CASE SCENARIO
A 75-year-old man with a history of coronary artery disease, hypertension, and diabetes, who underwent a hip replacement 2 weeks ago, presents to the emergency room with several days of diarrhea and 24 hours of increasing abdominal pain and distension. Over the past 3 days he has also had low-grade fevers and general malaise.
On examination he is febrile to 101.7°F and tachycardic. His abdomen is distended and diffusely tender to palpation, with guarding on the right side. His lab work is remarkable for a white blood cell (WBC) count of 21,000/μL and a Cr of 1.6 mg/dL.
EPIDEMIOLOGY
Colitis is a general term to describe inflammation of the colon from a variety of causes, including ischemia, infection, and inflammation. Each type of colitis has its own characteristic incidence, presentation, and systemic manifestations.
Ischemic Colitis
The incidence of ischemic colitis in the general population ranges from 4.5 to 44 cases per 100,000 person-years, with a slight predominance in women.1 Despite this low incidence, ischemic colitis is the most common manifestation of mesenteric ischemia, and especially affects the elderly.1
Infectious Colitis
Infectious colitis is caused by a variety of bacterial, viral, and parasitic pathogens. Important pathogens include Salmonella, Shigella, Campylobacter, Enterohemorrhagic Escherichia coli (EHEC), Entamoeba histolytica, Clostridium difficile, and cytomegalovirus (CMV).
C. difficile inhabits the intestinal tract of 1% to 3% of healthy adults and 20% of patients receiving antibiotics, but only a subset of these patients develop C. difficile colitis.2 Despite this, the clinical impact of C. difficile colitis cannot be underestimated. According to data from the United States Healthcare Cost and Utilization Project’s Nationwide Inpatient Sample, from 2000 to 2009 the incidence of C. difficile infection increased from 49.2 to 109.6 per 100,000 population.3 In 2009, an estimated 336,600 hospitalizations, nearly 1% of all hospital stays, were due to C. difficile colitis. The majority of patients affected were 60 to 70 years old, and in patients with a principal diagnosis of C. difficile colitis, the colectomy rate was 1.6%.4
Infection with cytomegalovirus (CMV), a member of the herpesvirus family, is very common throughout the world. Seroprevalence increases with age. In a US-based study among individuals aged 6 to 49 years, CMV seroprevalence increased from 38% in 6- to 11-year-olds to 58% in those aged 40 to 49 years.5 CMV seropositivity was independently associated with older age, female sex, foreign birthplace, low household income, high household crowding, and low household education.5 Initial infection in an immunocompetent host may go unnoticed, but patients who are immunocompromised by treatment with immunosuppressive medications or by illnesses that reduce cellular immunity, such as inflammatory bowel disease or human immunodeficiency virus (HIV) infection, are susceptible to CMV systemic disease including retinitis, pneumonia, encephalitis, hepatitis, and gastrointestinal tract ulceration. Acute systemic illness is particularly common in a CMV-negative transplant recipient who receives an organ from a CMV-positive donor.
Inflammatory Colitis
The most common types of inflammatory colitis are ulcerative colitis (UC) and Crohn’s colitis. UC, characterized by recurrent episodes of inflammation limited to the mucosal layer of the colon, has an incidence of 1.2 to 20.3 cases per 100,000 persons per year and a prevalence of 7.6 to 246.0 cases per 100,000 per year.6 Crohn’s disease, manifesting as transmural inflammation of the gastrointestinal tract, has an incidence of 0.03 to 15.6 cases per 100,000 persons per year and a prevalence of 3.6 to 214.0 cases per 100,000 per year.7 Inflammatory bowel disease is classically thought to adopt a bimodal age distribution, with the first peak in the second and third decades and a smaller peak in the sixth and seventh decades of life. There is a slight female predominance in Crohn’s disease and a slight male predominance in UC. Smoking is a strong risk factor for Crohn’s disease, particularly for recurrence after treatment, but appears to be inversely associated with UC. Approximately 80% of Crohn’s patients have small-bowel involvement, usually in the distal ileum, with one-third of patients having ileitis exclusively. Approximately 50% of Crohn’s patients have involvement of both the ileum and colon, and 20% have disease limited to the colon.7
Toxic Megacolon
Toxic megacolon is a serious complication most commonly associated with UC, but it can also occur with infectious colitis, ischemic colitis, volvulus, diverticulitis, and obstructive colon cancer. The incidence of toxic megacolon is difficult to determine, but has been most extensively reported in UC. In a series of 1236 patients admitted to the hospital over a 19-year period, toxic megacolon was present in 6% of patients—10% of UC admissions and 2.3% of Crohn’s disease admissions.8 In pseudomembranous colitis, toxic megacolon is reported to occur in 0.4% to 3% of patients.2 This number is expected to increase with the increasing prevalence of C. difficile colitis. In patients with HIV infection, CMV is the leading cause of toxic megacolon.
PATHOPHYSIOLOGY
Ischemic Colitis
Ischemic colitis occurs when the metabolic demand of the colon exceeds the available oxygen and nutrient supply and can result from vascular occlusion by thrombus or emboli, vascular spasm, or low flow. This manifests along a spectrum of findings, from transient self-limiting ischemia causing mucosal hemorrhage, to permanent disruption of the blood supply with transmural necrosis and perforation. Ischemic colitis most often occurs in the elderly, who may already have atherosclerotic disease with stenotic mesenteric vessels.
“Nonocclusive” colonic ischemia occurs in low-flow states, e.g., cardiogenic or hypovolemic shock, and typically affects the watershed areas of the colon such as the splenic flexure or rectosigmoid junction. In these cases, the colonic arteries are patent, but poor global perfusion results in ischemia. In contrast, in “occlusive” ischemia thrombus or embolus obstructs the ileocolic branches of the middle colic artery, causing ischemia of the cecum and proximal right colon. Etiologies of emboli include atrial fibrillation, valvular vegetations, or atheromatous plaque from thoracic aneurysms. Finally, the sigmoid colon may be compromised in patients after an aortic aneurysm repair with ligation or occlusion of the inferior mesenteric artery.
Infectious Colitis
C. difficile spreads by fecal-oral transmission and manifests as an infection of the colon by toxigenic strains when the normal intestinal flora has been disrupted by antibiotics or antineoplastic agents. C. difficile releases two potent exotoxins that mediate the colitis and diarrhea: toxin A (enterotoxin) and toxin B (cytotoxin). Both toxins inactivate regulatory pathways involved in cytoskeleton structure and signal transduction, and disrupt intercellular tight junctions. Toxin A causes inflammation leading to intestinal fluid secretion, mucosal injury, and inflammation. Toxin B is essential for the virulence of C. difficile and is approximately 10 times more potent than toxin A on a molar basis for mediating colonic mucosal damage.9 Since the early 2000s a hypervirulent strain, NAP1/BI/027, has emerged and has been implicated as the responsible pathogen in selected C. difficile outbreaks. This strain produces substantially larger quantities of toxins A and B in vitro than other C. difficile strains.9
CMV may be transmitted through multiple routes, including casual contact by exposure to virus shed from the upper respiratory tract and urine, blood or tissue exposure, sexual contact, in utero by exposure to secretions in the birth canal, or postnatally from breast milk. Resolution of active infection results in a latent state, in which CMV persists indefinitely in the host tissues. If the host’s immune system becomes compromised, latent virus reactivation can occur, with ulcerative changes in the colon followed by watery diarrhea. As the ulcers increase in depth, erosion into blood vessels can cause profuse bloody diarrhea. Over time, inflammatory polyps may develop, which, rarely, may obstruct the colon. Severe inflammation and vasculitis with vascular luminal thrombosis may lead to ischemia and transmural necrosis of the bowel, resulting in perforation and peritonitis. The hallmark of CMV infection is the histologic finding of intranuclear inclusions in the endothelial cells of the intestinal wall, consistent with herpesvirus infection. CMV infection may be confirmed using in situ hybridization or staining of intranuclear inclusions using CMV-specific antibodies linked to an indicator system (e.g., horseradish peroxidase, fluorescein). Numerous studies have shown increased colonic CMV reactivation in UC patients, particularly those with steroid-refractory disease.10
Inflammatory Colitis
UC is an idiopathic disorder characterized by relapsing and remitting mucosal and submucosal inflammation of the colon and rectum. It commonly begins in the rectum and extends proximally in a confluent fashion to involve the colon. Eighty percent of patients have predominantly distal disease, although 20% will develop pancolitis. Approximately 10% of UC patients will show evidence of fulminant colitis, which can progress to toxic megacolon.11
In contrast to UC, Crohn’s disease may affect any part of the GI tract from mouth to anus. The three main disease patterns are inflammatory, stricturing, and penetrating. Bowel inflammation extends from the mucosa through all layers of the bowel wall and occasionally penetrates adjacent structures (fistulizing disease). Twenty percent of patients have disease limited to the colon. In contrast to the consistent rectal involvement in patients with ulcerative colitis, one-half of Crohn’s disease patients with colitis have sparing of the rectum.12
Autoimmunity may play a role in both UC and Crohn’s disease. Crohn’s disease is associated with circulating antibodies against bacterial antigens (anti-I2, anti-OmpC, and anti-CBir1 antibodies) and fungal antigens (anti–Saccharomyces cerevisiae antibodies [ASCA]). In addition to antineutrophil cytoplasmic antibodies (pANCA), UC is characterized by circulating IgG1 antibodies against a colonic epithelial antigen that is shared with the skin, eye, joints, and biliary epithelium, the sites of extraintestinal manifestations in inflammatory bowel disease (IBD). Extraintestinal manifestations include pyoderma gangrenosum, erythema nodosum, apthous stomatitis, uveitis, episcleritis, peripheral arthritis, ankylosing spondylitis, sacroiliitis, primary sclerosing cholangitis, thromboembolic events, and nephrolithiasis.13
Toxic Megacolon
The pathophysiology of toxic megacolon is not fully understood, but is thought to involve severe inflammation extending through the colon wall, with damage and paralysis of the colonic smooth muscle layer and dilatation of the colon. The main characteristics are radiographic evidence of total or segmental colonic distension ≥6 cm, and bacterial translocation leading to bacteremia and systemic sepsis, which distinguishes toxic megacolon from other types of colonic dilatation such as Hirschsprung’s or Ogilvie’s syndrome.
CLINICAL PRESENTATION
The presentations of patients with ischemic, inflammatory, and infectious colitis often overlap. Therefore, patient comorbidities and clinical history play an important role in distinguishing the various types of colitis.
Ischemic Colitis
Signs and symptoms of ischemic colitis consist of abdominal pain accompanied by bloody diarrhea. The severity of the abdominal pain may vary, from vague to severe with peritonitis. Patients with chronic vascular insufficiency may exhibit post-prandial abdominal pain and weight loss, although this is more commonly seen in mesenteric ischemia affecting the small bowel. Embolic colonic ischemia often presents with acute-onset abdominal pain. Metabolic acidosis from lactate production is a sign of ischemia, but does not always correlate with extent of disease. Since the presentation of ischemic colitis is often nonspecific, the physician must have a high index of suspicion if a patient presents with abdominal pain and bloody diarrhea in the setting of peripheral vascular disease, atrial fibrillation, or a hypercoagulable state.
Infectious Colitis
C. difficile colitis also produces a wide spectrum of disease, from mild diarrhea to toxic megacolon and multisystem organ failure. C. difficile colitis must be considered in patients who were recently exposed to antibiotics, were recently hospitalized, or have a history of C. difficile infection. Patients often have watery diarrhea up to 10 or 15 times daily with lower abdominal pain and cramping, low-grade fever, and leukocytosis. These symptoms may begin on the first day of antibiotic use, but most commonly arise a week after antibiotic exposure. The manifestations of fulminant colitis typically include severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis (up to 40,000 WBC/μL). Importantly, C. difficile colitis can also present without diarrhea, particularly in more severe colitis with ileus secondary to a dilated, atonic colon. Other potential complications of fulminant colitis include toxic megacolon and bowel perforation.
Patients with a recent travel history or immunosuppression should undergo testing for other infectious etiologies, i.e., Yersinia, Shigella, etc. Additionally, CMV colitis should be suspected in any immunosuppressed patient, including transplant, inflammatory bowel disease, and HIV patients. CMV colitis can present with the nonspecific symptoms of diarrhea, fever, abdominal pain, and weight loss. Diarrhea may be bloody or non-bloody.
Inflammatory Colitis
Patients with UC often present with diarrhea, which may be bloody. Additional symptoms include colicky abdominal pain and tenesmus, along with fever and fatigue. The severity of symptoms may range from mild disease with four or fewer stools per day, with or without blood, to severe disease with 10 to 20 stools per day, severe cramps, and continuous bleeding. Patients with UC usually present with intermittent attacks of abdominal pain and bloody diarrhea that can last for weeks to months until treated.
The presentation of Crohn’s colitis is variable and includes fatigue, prolonged diarrhea with abdominal pain, weight loss, and fever. Gross bleeding is less frequent than in UC. The transmural inflammation of Crohn’s disease is also associated with the development of fistulas between the colon and small bowel, bladder, vagina, or skin. In a population-based study of patients with Crohn’s disease, the cumulative risk of any fistula was 33% at 10 years and 50% after 20 years.12 Transmural inflammation may also result in sinus tracts with a phlegmon or abscess and peritonitis. Perianal disease, including large skin tags, anal fissures, perirectal abscess, and anal fistula, occurs in more than one-third of patients with Crohn’s disease and can be a useful identifier of Crohn’s disease when the distinction between UC and Crohn’s colitis is not clear.
It is often difficult to differentiate between UC and Crohn’s colitis, and in 10% to 15% of patients with inflammatory bowel disease, the distinction cannot be made. These patients are given a diagnosis of “indeterminate colitis.”13 Table 12–1 lists distinguishing features of the two diagnoses.
