Emergency Medicine

Inflammatory Bowel Disease

The authors differentiate ulcerative colitis and Crohn's disease and identify the keys to diagnosis and management of each.

By Chad Listrom, MD, and Kurtis Holt, MD

Both primary care and emergency physicians can expect to encounter patients with inflammatory bowel disease (IBD), sometimes as an acute exacerbation of known disease and sometimes needing to be diagnosed. When given the proper medical care and treatment, the majority of these patients lead active lives and have productive careers despite the unremitting and chronic disease course of IBD. Initiating the proper diagnostic evaluation, being aware of the potential complications, understanding the treatment options, and involving the proper specialist consultants will increase success in the management of patients with IBD

Who gets inflammatory bowel disease and when does it occur?

Inflammatory bowel disease, which includes both ulcerative colitis (UC) and Crohn's disease (CD), is a chronic disease characterized by recurrent, acute exacerbations and remissions. The incidence of both UC and CD is approximately 5 per 100,000 globally and 10 per 10,000 in northern Europe and North America.

While the incidence of UC has remained constant, CD has steadily increased during the past 20 years. It may be slightly more prevalent in women, although gender has not been identified as an independent risk factor for the disease. A family history of IBD, however, has consistently been considered the single greatest risk predictor for IBD. Between 15% and 25% of individuals with IBD will have a first-degree relative who also has either UC or CD. A genetic component to the development of IBD is further supported by twin studies. Monozygotic twins have been shown to have much higher concordance for developing IBD than their dizygotic counterparts. Interestingly, smokers are twice as likely to develop CD, have more frequent relapses, and have more severe disease. With UC, the opposite is true: smokers have half the risk of nonsmokers, which has prompted studies investigating nicotine as a potential treatment option for UC.

The onset and diagnosis of IBD can occur at any time throughout life, but a bimodal distribution has been observed. Early adulthood, particularly ages 15 to 25, is typically when IBD presents, with a second smaller peak in the elderly.

Has the etiology of inflammatory bowel disease been discovered?

Despite advances in the understanding of the immune mechanisms involved with IBD, the etiology and actual cause of the disease remain elusive. Whether due to a persistent intestinal infection, a defective mucosal barrier in the intestinal lumen allowing unrestrained uptake of antigens, or an abnormal host response to native antigens, an inflammatory response is initiated in a genetically susceptible person. The process is continued by constant exposure to a particular microenvironment; normal intestinal bacteria have been shown to contribute to the continuing cascade of inflammation. Intestinal inflammatory cells produce pro-inflammatory molecules such as interleukin-1, tumor necrosis factor (TNF), and interleukin-12, which recruit more inflammatory cells, increase adhesion molecules in the vascular endothelium, cause tissue damage, and ultimately provoke the clinical manifestations of IBD.

Genetic deletions of anti-inflammatory regulators, interruption of normal T-cell homeostasis, and dysregulation of pro-inflammatory molecules can all lead to an IBD-like colitis in animal models, while evidence for a typical autoimmune disease is lacking. Multiple studies regarding the genetic predisposition for developing IBD have begun to demonstrate strong associations between particular human leukocyte antigens (HLAs) and IBD. For instance, the HLA-DR2 allele is associated with UC, while HLA-A2 and HLA-DR1 DQw5 are associated with CD. Because no single environmental trigger or gene complex has been identified, it is likely that multiple combinations of environmental factors and genetics can lead to the formation of IBD.

As the inflammatory process of IBD is further elucidated, novel therapies will become available. So far, treatment strategies using antibodies that block pro-inflammatory molecules in IBD, particularly TNF, have been encouraging.

What differentiates ulcerative colitis from Crohn's disease? What are the major complications of each disease?

Although UC and CD are similar in many ways and probably represent a spectrum of disease, several attributes distinguish them. Ulcerative colitis is characterized by a continuous inflammatory condition of the mucosa and submucosa that extends from the rectum to varying levels of colonic involvement, with sparing of the remainder of the gastrointestinal tract. Sole involvement of the rectum or rectosigmoid occurs in 40% to 50% of patients. Disease extends to the descending colon in 30% to 40%, and pancolitis is found in the remaining 20%. Colorectal cancer and toxic megacolon can occur with either disease but are much more common with UC. Toxic megacolon is generally considered the most serious complication of IBD. Patients are acutely ill, appear toxic, and have severe abdominal pain and distension. They are usually febrile, tachycardic, have an elevated white blood cell (WBC) count and erythrocyte sedimentation rate (ESR), and colonic dilation on plain radiography to more than 6 cm. Pneumatosis and perforation can occur without treatment, and medical management failures are common, with a strong likelihood of progression to colectomy.

The risk of colorectal cancer is correlated with the duration and severity of the disease. About 5% to 8% of UC patients will develop colorectal cancer within 20 years after diagnosis of their disease. Preventive options include prophylactic proctocolectomy, often after 10 years of diagnosis when the risk of cancer begins to escalate. Colonoscopy remains an important option for colorectal cancer surveillance. The American Cancer Society currently recommends colonoscopy every one to two years beginning eight years post-diagnosis, with biopsies taken at 10- to 12-centimeter intervals along the colon. The relationship between colorectal cancer and CD is not as strong, but the risk is believed to be approximately three times that of the baseline population. No surveillance guidelines for prophylaxis exist at this time.

Crohn's disease is characterized by frequent sparing of the rectum, can affect any portion of the gastrointestinal tract from mouth to anus, and occurs in a discontinuous manner with inflamed tissue interspersed among areas of normal tissue. Inflammation of the ileum (ileitis) is the most common pattern in CD, occurring in 30% of patients, followed by sole involvement of the colon in 20% and involvement of the large and small bowel in the remainder. Unlike UC, CD is a transmural inflammatory condition that can lead to multiple complications such as abscesses, strictures, obstruction, fistulas, and perianal manifestations (skin tags, erosions, ulcerations, and fissures). Physicians must be aware of the potential complications of CD because they may prompt patients to seek medical care and often necessitate hospital admission and surgical consultation.

What extra-gastrointestinal manifestations occur in inflammatory bowel disease?

Between 25% and 36% of patients with IBD will develop one or more extra-gastrointestinal manifestations. Arthralgias and arthritis occur frequently and may precede the onset of intestinal symptoms. They are usually transient, asymmetric, nondeforming, and typically involve inflammation of the large joints, including the knees, ankles, hips, and wrists in decreasing order of frequency. Symptoms typically parallel bowel disease activity and improve with treatment of intestinal inflammation.

There are many skin diseases associated with IBD, but the two most common are erythema nodosum and pyoderma gangrenosum. Erythema nodosum occurs in 9% of UC patients and 15% of CD patients while pyoderma gangrenosum occurs in 12% of UC patients and 1% to 2% of CD patients. The skin diseases associated with IBD are often diagnosed during times of bowel inflammation and respond to treatment of bowel symptoms, although pyoderma gangrenosum may require more aggressive treatment.

Conjunctivitis, episcleritis, and iritis or uveitis occur in 3% to 11% of patients with IBD. Conjunctivitis and episcleritis present with red eye but without pain or photophobia. Anterior uveitis or iritis will present with red eye, pain, photophobia, and possibly an abnormal pupillary light response and should be treated in consultation with an ophthalmologist. Ocular manifestations may precede diagnosis of IBD and may occur during exacerbations or when in remission.

Oral lesions occur in IBD with an incidence of approximately 6% to 20% in CD and 8% in UC. Recurrent aphthous ulcerations are the most common manifestation, although many other oral lesions have been observed, including granulomatous masses, cheilitis, and granulomatous sialadenitis. Symptoms may be severe and often impair nutrition and oral intake. Oral lesions are particularly present and symptomatic at times of intestinal inflammation and respond to treatment against intestinal disease. Additionally, topical hydrocortisone in pectin gelatin or carboxymethylcellulose and topical sucralfate may be effective for local symptom relief.

Hepatobiliary disease includes gallstones, steatosis, and primary sclerosing cholangitis, although there is little correlation between the incidence and type of hepatobiliary disorder and the severity of underlying colitis. Steatosis is the most common liver abnormality encountered with IBD, but it does not progress to hepatic inflammatory changes or chronic liver disease. Primary sclerosing cholangitis occurs in 1% to 4% of patients with IBD, most often with UC, and symptoms may include fatigue, jaundice, and pruritus. It is diagnosed with endoscopic retrograde cholangiopancreatography, and there is no effective treatment.

Cholelithiasis occurs in 13% to 34% of Crohn's patients with terminal ileum disease. This increased incidence is a direct result of distal ileal dysfunction with secretion of bile and interruption of the normal enterohepatic circulation of bile. Thromboembolic events, particularly deep venous thrombosis and pulmonary embolism, are due to a hypercoagulable state. Amyloidosis is an uncommon but well documented complication of IBD, particularly CD. When present, amyloidosis often involves the kidneys, causing nephrotic syndrome and renal failure. Nephrolithiasis and osteopenia are also increased in patients with IBD.

What are the presenting symptoms of inflammatory bowel disease and how is it diagnosed?

The presenting symptoms of IBD depend on the involved portion of the gastrointestinal tract. Rectal bleeding, urgency, and tenesmus indicate proctitis. Abdominal pain and cramping often are increased with advancing bowel involvement. Isolated right lower quadrant pain that mimics appendicitis may be present with ileitis, while epigastric pain and nausea indicate upper gastrointestinal tract involvement. Approximately one half of new-onset IBD patients will present acutely with fever, bloody diarrhea, and abdominal pain. Stool cultures and examination for ova and parasites are needed in new-onset patients to rule out infectious etiologies, including Salmonella, Shigella, Campylobacter, Yersinia, enterohemorrhagic Escherichia coli, and invasive amebiasis (serologies are often necessary). Clostridium difficile must be ruled out in patients recently taking antibiotics. Ischemic colitis and other causes of abdominal pathology such as cholecystitis, appendicitis, pancreatitis, and diverticulitis must also be considered, particularly in the elderly when the predominant symptom is abdominal pain.

The other half of new-onset IBD patients will have a subacute presentation with chronic diarrhea, intermittent rectal bleeding, crampy abdominal discomfort, poor weight gain or unexplained weight loss, and anemia. A delayed diagnosis is not uncommon in these patients because signs and symptoms are nonspecific. A double contrast barium enema was historically used as a diagnostic modality. Currently, colonoscopy is widely used to diagnose IBD, determine the extent of disease, monitor treatment response, and conduct surveillance for colorectal cancer. Ulcerative colitis typically will show uniform mucosal erythema or edema, shallow ulcers, and circumferential inflammation with an abrupt transition from inflamed to normal mucosal tissue. Alternatively, CD will exhibit a patchy erythema or edema, aphthoid ulcers, longitudinal and transverse fissures, and an asymmetric, discontinuous distribution of inflammation. Even after a thorough diagnostic evaluation, approximately 5% to 10% of patients will be either misdiagnosed or unable to be accurately diagnosed with CD versus UC.

What is the diagnostic work-up and treatment for an acute inflammatory bowel disease exacerbation?

Patients with known IBD will also present to their physician with acute exacerbations of their chronic illness. Inflammatory bowel disease can be classified into mild, moderate, and severe disease, which can help guide treatment. Mild disease is characterized by less than four stools per day and no systemic manifestations, moderate disease by four to six stools per day with or without blood and minimal systemic disturbances, and severe disease by more than six stools per day with blood, heart rate above 90, ESR greater than 30 mm/hr, and fever. A WBC count, ESR, and C-reactive protein level are useful lab tests that correlate with disease. Additionally, a microcytic anemia, hypoproteinemia, and thrombocytosis may be noted. Serum vitamin B₁₂ levels should be periodically monitored in patients with severe ileal disease or past ileal resections to rule out pernicious anemia as a result of vitamin B₁₂ malabsorption and deficiency.

Any acutely ill patient should have a plain abdominal film performed to evaluate for toxic megacolon, perforation, and obstruction. Findings indicative of inflammation include increased bowel wall thickening and loss of haustral markings. Severely ill patients and those who have not improved with outpatient management require hospital admission. Treatment consists of intravenous (IV) fluids, electrolyte replacement, gastrointestinal decompression, and either IV hydrocortisone or methyprednisolone. Antibiotics are usually reserved for bowel perforations or toxic megacolon and are chosen to cover anaerobes and gram-negative bacteria. Due to the increased thromboembolic events in IBD, prophylaxis for deep vein thrombosis with pneumatic compression, subcutaneous heparin, or both, is an important aspect of in-hospital management.

How is inflammatory bowel disease medically managed on an outpatient basis?

Most patients with IBD have mild to moderate disease that responds to outpatient medical management, with the location of disease dictating which regimen is indicated. Sulfasalazine (sulfapyridine + 5-aminosalicylic acid) remains the cornerstone therapy for UC and Crohn's colitis. The active component, 5-aminosalicylic acid, is cleaved from the parent drug in the colon, making sulfasalazine an effective drug for colonic disease but ineffective for Crohn's small bowel inflammation. Three-fourths of patients with mild to moderate active disease will obtain remission on a dose regimen of 4 to 6 gm daily and 2 gm daily when in remission.

Sulfasalazine doses are limited by its side effects such as nausea, vomiting, heartburn, reversible semen abnormalities, and particularly headache. These effects can be minimized by gradually increasing the dose and taking the medication with meals. The newer oral 5-aminosalicylic acids, such as mesalamine, have fewer side effects but maintain a similar efficacy. With limited left-sided colonic disease or proctitis, 5-aminosalicylic acid rectal suppositories have similar efficacy to oral medications and have been shown to be superior to steroid enemas for inducing and maintaining remission.

Although corticosteroids usually have no value in maintaining remission, they are the standard therapy for severe, active disease. They induce remissions in 66% to 78% of active CD patients, 60% to 80% for moderately severe UC, and 40% to 55% with severe UC. An effective regimen is 40 to 60 mg of prednisone daily for 10 to 14 days, followed by a steroid taper. Patients with severe disease or frequent exacerbations may require chronic steroids to maintain disease remission. The lowest dose necessary to control symptoms should be used, and alternate-day therapy may be attempted to minimize toxicity and side effects of chronic steroid use. Patients requiring chronic steroids are at risk for adrenal suppression, infection, myopathies, hypertension, glucose intolerance, osteoporosis, and aseptic necrosis of the femoral head.

Antibiotics such as metronidazole and ciprofloxacin have been studied as therapy for IBD. Metronidazole has little benefit in active UC or in maintaining remissions. A daily dose of 10 to 20 mg/kg is effective for treatment of perianal CD. The physician and patient should be aware that paresthesias are common with long-term therapy. Ciprofloxacin has shown promise as an adjunct to mesalamine and corticosteroids in active UC and CD.

What if standard therapy is ineffective?

About 20% of CD patients and 20% to 40% of UC patients will need major immunosuppressive drugs at some time. Indications for advancement of medical treatment include failure to respond to first-line medical therapy, steroid-related side effects, and chronic steroid dependence. Azathioprine and its active metabolite, 6-mercaptopurine, have been shown to be beneficial for UC with either steroid refractoriness or dependence. Approximately 66% of patients will respond; the effectiveness in CD is less pronounced but may still be of some benefit. Treatment times of 12 weeks or more are often required before a therapeutic effect is noted. Side effects include bone marrow suppression, pancreatitis, allergic reactions, and nausea, which may lead to discontinuation of treatment in approximately 6% to 9% of patients.

Methotrexate has not been shown to be particularly effective in UC but may be of some benefit in CD. Patients with steroid-refractory or -dependent CD may have clinical improvement with six to nine weeks of treatment. Discontinuation of treatment secondary to side effects is common, however.

Cyclosporine may play a role in severe disease facing colectomy or as a temporary bridge to a less urgent surgical procedure. Total parenteral nutrition may also be effective in CD for obtaining remission when other medical therapies have failed. Advancement of medical therapy and the use of immunosuppressive drugs when IBD is difficult to control should include consultation and referral to a gastroenterologist. As research continues to elucidate the inflammatory process in IBD, more specific therapies will become available as effective treatments. Currently, a monoclonal IgG antibody to TNF, infliximab, has been shown to be efficacious in active, refractory CD and Crohn's fistulas. Forty-one percent of CD patients will have a clinical response 12 weeks after a single injection of infliximab.

When is surgery necessary?

Despite maximal medical management, one-third of UC patients and two-thirds of CD patients ultimately require resectional surgery. Ulcerative colitis is potentially curable with surgery, whereas in CD surgery is typically palliative and recurrence at the anastomotic site is common. Indications for surgery include failed maximal medical management, toxic megacolon unresponsive to medical management within 24 to 48 hours, severe medication side effects, malignancy, and obstructions or strictures.