Inflammatory Bowel Disease 

Inflammatory bowel disease (IBD) is an idiopathic disease, probably involving an immune reaction of the body to its own intestinal tract. The 2 major types of IBD are ulcerative colitis (UC) and Crohn disease (CD). As the name suggests, ulcerative colitis is limited to the colon. Crohn disease can involve any segment of the gastrointestinal (GI) tract from the mouth to the anus (see the images below).

There is a genetic predisposition for IBD. Patients with IBD are more prone to the development of malignancy. (See Prognosis.) Crohn disease can affect any portion of the GI tract from the mouth to the anus, involves "skip lesions," and is transmural. (See Background.)

Ulcerative colitis and Crohn disease share many extraintestinal manifestations, although some of these tend to occur more commonly with either one. Extraintestinal manifestations of IBD include iritis, episcleritis, arthritis, and skin involvement, as well as pericholangitis and sclerosing cholangitis. Although both ulcerative colitis and Crohn disease have distinct pathologic findings, a significant percentage of patients with IBD have indeterminate findings. Systemic symptoms are common in IBD and include fever, sweats, malaise, and arthralgias.

The rectum is always involved in ulcerative colitis, and the disease primarily involves continuous lesions of the mucosa and the submucosa. Both ulcerative colitis and Crohn disease usually have waxing and waning intensity and severity. When the patient is actively symptomatic, indicating significant inflammation, the disease is considered to be in an active stage (the patient is having a flare of the IBD). (See Clinical Presentation.)

The stovepipe sign seen on barium enema is due to chronic ulcerative colitis, in which the colon becomes a rigid foreshortened tube that lacks its usual haustral markings. In Crohn disease, the string sign (a narrow band of barium flowing through an inflamed or scarred area) in the terminal ileum are typically observed on radiographs. (See Workup.)

When the degree of inflammation is less (or absent) and the patient is usually asymptomatic, then the patient's disease is considered to be in remission. In most cases, symptoms correspond well to the degree of inflammation present for either disease, although this is not universally true. In some patients, objective evidence for disease activity should be sought before administering medications with significant adverse effects (see Medication), because patients with inflammatory bowel disease can have a coexisting irritable bowel syndrome.

Although ulcerative colitis and Crohn disease have significant differences, many (but not all) of the treatments available for one condition are also effective for the other. Surgical intervention for ulcerative colitis is curative for colonic disease and potential colonic malignancy, but it is not curative for Crohn disease. (See Treatment and Management.)

The pathophysiology of IBD is under active investigation. The common end pathway is inflammation of the mucosal lining of the intestinal tract, causing ulceration, edema, bleeding, and fluid and electrolyte loss.

Many inflammatory mediators have been identified in IBD, and considerable evidence suggests that these mediators play an important role in the pathologic and clinical characteristic of these disorders. Cytokines, released by macrophages in response to various antigenic stimuli, bind to different receptors and produce autocrine, paracrine, and endocrine effects. Cytokines differentiate lymphocytes into different types of T cells. Helper T cells, type 1 (Th-1), are associated principally with Crohn disease, whereas Th-2 cells are associated principally with ulcerative colitis. The immune response disrupts the intestinal mucosa and leads to a chronic inflammatory process.^[1]

Several animal models are used to study IBD. A local irritant (eg, acetic acid, trinitrobenzene sulfonic acid) can be inserted via an enema into the colon of rats or rabbits to induce a chemical colitis. An interleukin-10 (IL-10) knockout mouse has been genetically engineered to have some characteristics similar to those of a human with IBD. The cotton-top marmoset, a South American primate, develops a colitis very similar to ulcerative colitis when the animal is subjected to stress.

Ulcerative colitis

In ulcerative colitis, inflammation begins in the rectum and extends proximally in an uninterrupted fashion to the proximal colon, eventually involving the entire length of the large intestine. The rectum is always involved in ulcerative colitis, and no "skip areas" (ie, normal areas of the bowel interspersed with diseased areas) are present, unlike Crohn disease.

The disease remains confined to the rectum in approximately 25% of cases, and in the remainder of cases, ulcerative colitis spreads proximally and contiguously. Pancolitis occurs in 10% of patients. The small intestine is never involved, except when the distal terminal ileum is inflamed in a superficial manner, referred to as backwash ileitis. Even with less than total colonic involvement, the disease is strikingly and uniformly continuous. As ulcerative colitis becomes chronic, the colon becomes a rigid foreshortened tube that lacks its usual haustral markings, leading to the lead pipe appearance observed on barium enema.

Crohn disease

Crohn disease can affect any portion of the GI tract from the mouth to the anus and causes 3 patterns of involvement: inflammatory disease, strictures, and fistulas. This disease consists of segmental involvement by a nonspecific granulomatous inflammatory process. The most important pathologic feature of Crohn disease is that it is transmural, involving all layers of the bowel, not just the mucosa and the submucosa, which is characteristic of ulcerative colitis. Furthermore, Crohn disease is discontinuous, with skip areas interspersed between one or more involved areas. See the image below.

Late in the disease, the mucosa develops a cobblestone appearance, which results from deep, longitudinal ulcerations interlaced with intervening normal mucosa. The 3 major patterns of involvement in Crohn disease are disease in the ileum and cecum (40% of patients); disease confined to the small intestine (30% of patients); and disease confined to the colon (25% of patients). Rectal sparing is a typical but not constant feature of Crohn disease. However, anorectal complications (eg, fistulas, abscesses) are common. Much less commonly, Crohn disease involves the more proximal parts of the GI tract, including the mouth, tongue, esophagus, stomach, and duodenum.

The incidence of gallstones and kidney stones is increased in Crohn disease because of malabsorption of fat and bile salts. Gallstones are formed because of increased cholesterol concentration in the bile, caused by a reduced bile salt pool.

Patients who have Crohn disease with ileal disease or resection are also likely to form calcium oxalate kidney stones. With the fat malabsorption, unabsorbed long-chain fatty acids bind calcium in the lumen. Oxalate in the lumen is normally bound to calcium. Calcium oxalate is poorly soluble and poorly absorbed; however, if calcium is bound to malabsorbed fatty acids, oxalate combines with sodium to form sodium oxalate, which is soluble and is absorbed in the colon (enteric hyperoxaluria). The development of calcium oxalate stones in Crohn disease requires an intact colon to absorb oxalate. Patients with ileostomies generally do not develop calcium oxalate stones.

The triggering event for the activation of the immune response in IBD has yet to be identified. Possible factors related to this event include a pathogenic organism (as yet unidentified), an immune response to an intraluminal antigen (eg, protein from cow milk), or an autoimmune process whereby an appropriate immune response to an intraluminal antigen and an inappropriate response to a similar antigen is present on intestinal epithelial cells (ie, alteration in barrier function).

No mechanism has been implicated as the primary cause, but many are postulated as potential causes. The lymphocyte population in persons with IBD is polyclonal, making the search for a single precipitating cause difficult. In any case, activation of the immune system leads to inflammation of the intestinal tract, both acute (neutrophilic) and chronic (lymphocytic, histiocytic).

The E3N prospective study found that high animal protein intake (meat or fish) was associated with a higher risk of inflammatory bowel disease.^[2]

Genetics

Persons with IBD have a genetic predisposition (or, perhaps, susceptibility) for the disease^[3] and a great deal of research has been performed to discover potential genes linked to IBD. An early discovery was on chromosome 16 (IBD1 gene), which led to the identification of the NOD2 gene (now called CARD15) as the first gene clearly associated with IBD (as a susceptibility gene for Crohn disease). Studies have also provided strong support for IBD susceptibility genes on chromosomes 5 (5q31) and 6 (6p21 and 19p). NOD2/CARD15 is a polymorphic gene involved in the innate immune system. The gene has more than 60 variations, of which 3 play a role in 27% of patients with Crohn disease, primarily in patients with ileal disease. With all of these potential genes, it is important to note that they appear to be permissive (ie, allow IBD to occur) but not causative (ie, just because the gene is present does not necessarily mean the disease will develop).

First-degree relatives have a 5- to 20-fold increased risk of developing IBD compared with persons from unaffected families. The child of a parent with IBD has a 5% risk of developing IBD. Twin studies show a concordance of approximately 70% in identical twins versus 5-10% in nonidentical twins. Of patients with IBD, 10-25% is estimated to have a first-degree relative with the disease. Monozygous twin studies show a high concordance for Crohn disease but less so for ulcerative colitis.

Smoking

The risk of developing ulcerative colitis is higher in nonsmokers and former smokers than in current smokers. The onset of ulcerative colitis occasionally appears to coincide with smoking cessation. This does not imply that smoking would improve the symptoms of ulcerative colitis; interestingly, some success in the use of nicotine patches has been reported. Instead, patients with Crohn disease have a higher incidence of smoking than the general population, and those patients with Crohn disease who continue to smoke appear to be less likely to respond to medical therapy.

United States statistics

Before 1960, the incidence of ulcerative colitis was several times higher than that of Crohn disease. The latest data suggest that the current incidence of Crohn disease is approaching that of ulcerative colitis, although this change may reflect improved recognition and diagnosis of Crohn disease.

An estimated 1-2 million people in the United States have ulcerative colitis or Crohn disease, with an incidence rate of 70-150 cases per 100,000 individuals. Among persons of European descent in Olmstead County, Minnesota, the incidence of ulcerative colitis was 7.3 cases per 100,000 people per year with a prevalence of 116 cases per 100,000 people, and the incidence of Crohn disease was 5.8 cases per 100,000 people per year, with a prevalence of 133 cases per 100,000 people.^{[4, 5]}

The prevalence of IBD among Americans of African descent is estimated to be the same as the prevalence among Americans of European descent, but the prevalence is lower among Americans of Asian and Hispanic descent. The incidence of IBD among white individuals is approximately 4 times that of other races, with the highest rates reported to be in Jewish populations, followed by non-Jewish white populations. The prevalence rates of IBD among the American Jewish population are approximately 4-5 times that of the general population. In fact, however, data suggest that the incidence rates in non-Jewish, black, and Hispanic populations are increasing.

The male-to-female ratio is approximately equal for ulcerative colitis and Crohn disease, with females having a slightly greater incidence. Both diseases are most commonly diagnosed in young adults (ie, late adolescence to the third decade of life).

The age distribution of newly diagnosed IBD cases is bell-shaped; the peak incidence occurs in people in the early part of their second decade of life, with the vast majority of new diagnoses made in people aged 15-40 years. A second, smaller peak in incidence occurs in patients aged 55-65 years. However, children younger than 5 years and elderly persons are occasionally diagnosed. Of patients with IBD, 10% are younger than 18 years.

International statistics

The incidence of IBD varies within different geographic areas, with the highest rates assumed to be in developed countries and lowest in developing regions; colder climate regions and urban areas have a greater rate of IBD than those of warmer climates and rural areas. Internationally, the incidence of IBD is approximately 2.2-14.3 cases per 100,000 person-years for ulcerative colitis and 3.1-14.6 cases per 100,000 person-years for Crohn disease. Overall, the combined incidence for IBD is 10 cases per 100,000 annually.^{[4, 5]}

Multiple studies on mortality in patients with IBD have been conducted from regions throughout the world. The standardized mortality ratio for IBD generally ranges from approximately 1.4 times the general population (Sweden) to 5 times the general population (Spain). In general, the 95% confidence intervals suggest that the increase in relative risk is real.

Ulcerative colitis and Crohn disease have approximately equal mortality rates. Although the mortality from ulcerative colitis has decreased over the past 40-50 years, with one study reporting a standardized mortality ratio of 0.6 in Florence, Italy, the vast majority of studies indicate a small but significant increase in mortality associated with IBD. The most frequent cause of death in persons with IBD is the primary disease, followed by malignancy, thromboembolic disease, peritonitis with sepsis, and complications of surgery.

Patients with IBD are more prone to the development of malignancy. Persons with Crohn disease have a higher rate of small bowel malignancy. Patients with pancolitis, particularly ulcerative colitis, are at a higher risk of developing colonic malignancy after 8-10 years of disease. The current standard of practice is to screen these patients with colonoscopy at 2-year intervals once they have had the disease for that duration. If a patient refuses appropriate screening, document it in the medical record.

Long-term morbidity can also result from complications of medical therapy, especially long-term steroids.

Ulcerative colitis

The average patient with ulcerative colitis has a 50% probability of having another flare during the next 2 years. However, the range of experiences is very broad; some patients may only have one flare over 25 years (as many as 10%), and others may have almost constant flares (much less common). A small percentage of patients with ulcerative colitis have a single attack and no recurrence. Typically, however, remissions and exacerbations are characteristic of this disease, with acute attacks lasting weeks to months.

Patients with ulcerative colitis limited to the rectum and sigmoid at the time of diagnosis have a greater than 50% chance of progressing to more extensive disease and a 12% rate of colectomy over 25 years. More than 70% of patients presenting with proctitis alone continue to have disease limited to the rectum over 20 years, and most patients who develop more extensive disease do so within 5 years of diagnosis. Of patients with ulcerative colitis involving the entire colon, 60% eventually require colectomy, whereas very few of those with proctitis require colectomy. Of interest, most surgical interventions are required in the first year of disease, and the annual colectomy rate after the first year is 1% for all patients.

Surgical resection for ulcerative colitis is considered curative for this disease, although postoperative pouchitis may occur in some patients. Of note, pouchitis is far more common in patients who have had a colectomy for ulcerative colitis than in those who have had a colectomy for other reasons (eg, familial adenomatous polyposis).

A generally accepted postulation is that the risk of colorectal cancer is not significantly higher in persons with ulcerative colitis than in the general population until several years after diagnosis. Beyond 8-10 years after diagnosis, the risk of colorectal cancer increases by 0.5-1.0% per year. Data suggest that surveillance colonoscopies with random biopsies reduce mortality from colorectal cancer in patients with ulcerative colitis, primarily by allowing the detection of carcinoma at an earlier Duke stage.

Crohn disease

The clinical course of Crohn disease is much more variable than that of ulcerative colitis, and it is independent of the anatomic location and extent of disease. Periodic remissions and exacerbations are the rule in Crohn disease. A patient in remission has a 42% likelihood of being free of relapse for 2 years and only a 12% likelihood of being free of relapse for 10 years. Over a 4-year period, approximately 25% of patients remain in remission, 25% have frequent flares, and 50% have a course that fluctuates between periods of flares and remissions.

Approximately 50% of patients with Crohn disease require surgical intervention. Of patients who undergo surgery, 50% require a second operation, and half of the patients who undergo a second operation will undergo a third. The rate of disease recurrence is 25-50% within 1 year for patients whose condition has responded to medical management; this rate is higher for patients who require surgery.

Surgery for Crohn disease is generally performed for complications (eg, stricture, stenosis, obstruction, fistula, bleeding) rather than for the inflammatory disease itself. However, although surgery is an important treatment option for Crohn disease, patients should be aware that it is not curative and that disease recurrence after surgery is the rule. Postsurgery, the frequency of recurrence of Crohn disease is high, generally in a pattern mimicking the original disease pattern, often on one or both sides of the surgical anastomosis. Endoscopic evidence of recurrent inflammation is present in 93% of patients 1 year after surgery for Crohn disease.

Overall, the patient's quality of life with Crohn disease generally is lower than that of individuals with ulcerative colitis. Data suggest that persons with Crohn colitis involving the entire colon have a risk of developing malignancy equal to that of persons with ulcerative colitis; however, the risk for most patients with Crohn disease is much smaller (albeit poorly quantified). Death usually occurs as a consequence of surgery, pulmonary embolus, or sepsis. Intestinal cancer may become a more important long-term complication in patients with Crohn disease because of longer survival.

Patients with inflammatory bowel disease (IBD) benefit tremendously from education about their disease. As a chronic, often lifelong, disease that is frequently diagnosed in young adulthood, increasing patient knowledge improves medical compliance and assists in the management of symptoms.

The Crohn's & Colitis Foundation of America is the most prominent organization in the United States that can directly provide educational materials for patients. This organization also supplies physicians with educational brochures at no cost upon request.

Encourage the patient to join an IBD support group, such as the Crohn's and Colitis Foundation of America (386 Park Avenue South, 17th Floor; New York, NY 10016; 1-800-932-2423).

For excellent patient education resources, visit eMedicine's Crohn Disease Center and Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles Inflammatory Bowel Disease, Crohn Disease, Crohn Disease FAQs, and Irritable Bowel Syndrome.