The IBDs, Crohn disease and ulcerative colitis, are chronic inflammatory illnesses of the gastrointestinal tract. Although significant advancements have been made in our understanding of the pathogenesis of these conditions, their ultimate cause remains idiopathic. The immunologic basis of IBD is discussed in Chapter 2. This chapter addresses the diagnosis and medical treatment of IBD. Surgical considerations are discussed in detail in Chapter 4.

A. Epidemiology

Crohn disease and ulcerative colitis have low incidences of new diagnosis; however, as a chronic condition typically diagnosed in the young, IBD has a relatively high prevalence. Estimates of incidence and prevalence vary among studies, with significant geographic and socioeconomic variations. The incidence of ulcerative colitis in North America is estimated to be 8–15 per 100,000 persons, with a prevalence of 170–230 per 100,000. Crohn disease has an estimated incidence of 5–15 per 100,000 and prevalence of 140–200 per 100,000. An increased incidence and prevalence of both forms of IBD is found in developed nations, northern locale (at least within the northern hemisphere), and urban environments; among Caucasians; and among persons of Jewish ethnicity. In industrialized countries, the incidence of Crohn disease has risen significantly over the past half century, whereas that of ulcerative colitis has remained relatively steady. In developing countries, the incidence of both forms of IBD has dramatically risen.

IBD typically presents at a relatively young age, often in adolescence. The median age of diagnosis for Crohn disease and ulcerative colitis is the third and fourth decades of life, respectively. Studies have suggested a second, smaller peak in incidence of IBD in the sixth and seventh decades, although this association is clearer for ulcerative colitis than for Crohn disease.

B. Etiology

The cause of IBD remains elusive, although interplay of genetic, microbial, and immunologic factors clearly exists. Twin and familial studies demonstrate a component of genetic susceptibility. However, the concordance rates among monozygotic twins for ulcerative colitis (6–18%) and Crohn disease (~50%) indicate that genetics play a relatively minor role in disease manifestation. Presumably, specific mutations confer susceptibility to IBD but are not sufficient per se. Various susceptibility genes have been identified, including NOD2/CARD15 on chromosome 16 and IL23R on chromosome 1, in Crohn disease. Both play integral roles in immune regulation within the gut. At the same time, mutations in these genes are present in only a minority of Crohn disease cases. Clearly, other less well-described dysregulations in the gut immune defense systems exist. A more complete discussion of the immunopathology of IBD can be found in Chapter 2.

Animal studies have demonstrated that the presence of commensal gut bacteria is necessary for IBD to occur. In theory, the subsequent enteritis or colitis results from a dysregulated or inappropriate immune response to flora tolerated by healthy individuals. Other environmental factors appear important as well. Cigarette smoking increases the risk for Crohn disease but is protective for ulcerative colitis. Both oral contraceptive and nonsteroidal anti-inflammatory medications have been implicated as risk factors for IBD, although the association remains controversial. Various diets have been proposed as causes or remedies for IBD, but no rigorous scientific evidence supports their use.

A. Crohn Disease

The inflammation in Crohn disease is typically transmural. This frequently leads to complications from perforating disease or from progressive fibrosis and stricturing. Crohn disease can thus be thought of as fitting one of three phenotypes: inflammatory, stricturing, or perforating disease (the latter including abscesses and fistulae). Disease behavior is not necessarily constant in an individual patient. Indeed, inflammatory disease frequently progresses to penetrating disease, and then to fibrosis and stricturing.

Unlike ulcerative colitis, Crohn disease may affect any part of the alimentary canal, and may do so in a nonconfluent (so-called skip lesion) pattern. Nearly half of all patients with Crohn disease have inflammation localized to the terminal ileum and cecum (Table 3–1). Isolated small bowel or colonic involvement is also common. Crohn disease of the esophagus, stomach, or duodenum is rare, and virtually unheard of in the absence of small bowel or colonic disease. Perianal disease, including abscesses and fistulae, is commonly encountered, particularly in conjunction with terminal ileal disease.

1. Symptoms and signs

The onset of symptoms in Crohn disease is typically insidious, and the subsequent clinical course is highly variable. For the majority of patients, the clinical course is characterized by recurring episodes of symptomatic disease interspersed with periods of remission. Abdominal pain and diarrhea are the most typical symptoms. Unlike ulcerative colitis, the diarrhea in Crohn disease is often nonbloody. Fever and weight loss are common. As a general rule, the location and phenotype of disease (inflammatory, stricturing, or perforating), along with the severity of inflammation, dictate a patient’s symptoms and signs.

Complications from fistulizing disease are common. Pain and drainage of purulent or fecal material are characteristic of perianal fistulae. Fistulae from the gut may cause a variety of symptoms, depending on the sites of origin and other organ(s) involved: gut—diarrhea, weight loss; skin—drainage; vagina—drainage; bladder—pneumaturia. Stricturing disease causes obstructive symptoms of pain, abdominal distention, nausea, and vomiting. Extraintestinal manifestations are frequently encountered with Crohn disease (as with ulcerative colitis) and are discussed in more detail below.

Signs of Crohn disease include abdominal tenderness, most classically in the right lower quadrant. An abdominal mass may be palpable. Temporal wasting and cachexia indicate significant malnutrition. Typical symptoms of small bowel obstruction (distention, tympany, high-pitched bowel sounds) may be present in stenosing disease. Perianal and cutaneous fistulae are readily identified on a careful perineal and skin examination.

2. Laboratory findings

No single laboratory test is diagnostic or specific for Crohn disease. Patients are typically at least mildly anemic, often with iron deficiency. Leukocytosis and thrombocytosis are common and typically reflect systemic inflammation. Serum albumin may be low in the case of protein-losing enterocolitis or in malnutrition. Malabsorption due to inflammation, bacterial overgrowth, or surgical resection may lead to diminished levels of various minerals (serum calcium and magnesium) and vitamins (B₁₂, D, and folate). C-reactive protein (CRP)—and, to a lesser extent, erythrocyte sedimentation rate (ESR)—are nonspecific markers of inflammation that are frequently elevated in Crohn disease.

Stool studies may reveal excess fat, indicative of malabsorption, or fecal leukocytes, indicative of gut inflammation. Stool studies should be negative for infectious pathogens, including standard bacterial pathogens, Clostridium difficile, and ova and parasites.

Various serologic markers have been linked with Crohn disease, including antibodies to the yeast Saccharomyces cerevisiae (ASCA), to bacterial proteins Omp-C and I2, and to clostridial flagellin, CBir-1. Several antibodies to bacterial carbohydrates, including ALCA, ACCA, and AMCA, have been studied but are not yet commercially available. Antineutrophil cytoplasmic antibodies (ANCA, P-subtype) are associated with both ulcerative colitis and Crohn colitis. As individual tests, these markers have limited diagnostic accuracy, but in select situations may be helpful in distinguishing Crohn disease from other inflammatory conditions.

New stool tests, fecal lactoferrin and calprotectin, are available that can help distinguish IBD from irritable bowel syndrome (IBS) (conditions that often have overlapping symptoms), potentially gauge disease activity, predict flare, and monitor and/or assess response to treatment. Lactoferrin is the major component of secondary granules in neutrophils and inhibits bacterial proliferation by iron binding. It is stable in the stool for 7 days. Calprotectin is present in neutrophils, monocytes, and macrophages. It comprises 60% of the cytosolic protein in neutrophils and is stable in the stool for 7 days. Both appear to be promising markers for monitoring therapy as well as surrogates for mucosal healing. Insurance coverage for these tests, unfortunately, remains a major barrier. Future drug trials are incorporating these markers and will hopefully lead to improved coverage.

More than 60 distinct susceptibility loci for IBD have been identified, and advances in the technology for analyzing genetic information have improved dramatically. These have allowed for the identification of over 40 genes associated with IBD including multiple genes that regulate the innate immune response. Five genes, including NOD2, have been identified as regulating innate immune function in the pathogenesis of Crohn disease. Nine genes involved in Crohn disease have been implicated in dysregulation of adaptive immunity. Thirteen genes have been associated with ulcerative colitis by gene array studies. The NOD2 (formerly CARD15) gene was the first to be well characterized, and its presence can predict the development of penetrating and fistulizing Crohn disease. IL-23R has been associated with both Crohn disease and ulcerative colitis and recently has been demonstrated to predict response to infliximab in ulcerative colitis patients. Recent studies have shown that using whole-blood gene array is a promising technology for distinguishing Crohn disease from ulcerative colitis and may have potential use in differentiating severity of disease and response to therapy.

3. Imaging studies

Standard abdominal plain films are useful for detecting obstructive disease and megacolon, but otherwise have a limited role in imaging Crohn disease. Small bowel series are useful for imaging small bowel mucosal disease, including strictures, ulcerations, and fistulae. Enteroclysis, although more sensitive, is limited by patient discomfort, increased radiation exposure, and its technically demanding nature. Barium enema remains an option for imaging colonic disease, especially to help delineate obstructive or fistulizing disease.

Computed tomography (CT) of the abdomen and pelvis has revolutionized the imaging of Crohn disease by allowing imaging of the bowel wall itself, as well as extraluminal disease such as abscesses or inflammatory masses. Common abnormalities of the gut include thickening and excessive mesenteric fat proliferation (so-called creeping fat). CT enterography, which uses a special low-density oral contrast, combines the advantages of CT and small bowel series by allowing detailed pictures of the small bowel mucosa, while at the same time imaging the extraintestinal abdomen. Three-dimensional CT reconstruction allows imaging of complicated transmural disease (see Figure 9–10). CT colonography has developed as a technology, but its role in Crohn disease remains limited in comparison to colonoscopy.

Magnetic resonance enterography (MRE) has been increasingly used. Studies have shown MRE to have better detection of mild disease than CT enterography (CTE) and slightly improved detection of wall thickening and enhancement. No significant difference was seen for moderate to severe disease. Other significant advantages include lack of ionizing radiation and, importantly, comprehensive evaluation of the perianal region. Disadvantages include higher cost compared to CTE and additional time needed to perform the study. Although not yet widely available, positron emission tomography (PET)/CTE in which glucose transporters are overexpressed in inflamed segments may show improved detection of lesions, better severity stratification, and improved monitoring of therapy.

Colonoscopy remains a mainstay in the assessment of Crohn disease, as it allows direct visualization of the bowel mucosa and sampling of tissue. Hallmark findings include ulcerations, erythema, granularity, and strictures. Pseudopolyps may be present. Ileal ulceration and skip lesions help distinguish Crohn disease from ulcerative colitis. The rectum is often spared. Fistulae are often difficult to locate endoscopically, and are best seen by contrast studies or magnetic resonance imaging (MRI). Endoscopic ultrasound, as previously mentioned, is useful in delineating perianal disease. Enteroscopy occasionally allows visualization of proximal small bowel lesions.

Capsule (“pill”) endoscopy has been revolutionary in terms of allowing direct visualization of the small bowel in Crohn disease. The most common finding is ulceration, ranging from shallow aphthous-type to deep “punched-out” lesions. Strictures may also be encountered, occasionally causing pill retention and subsequent obstruction.

B. Ulcerative Colitis

Unlike Crohn disease, inflammation in ulcerative colitis is limited to the mucosal layer of the colon. The rectum is virtually always involved, with inflammation extending proximally in a confluent fashion. The extent of proximal involvement is variable. A significant proportion of patients have disease confined to the rectum (ulcerative proctitis). Roughly one-third of patients have proctosigmoiditis, and the majority of patients have gross colitis only distal to the splenic flexure. Approximately one-third of patients have disease that extends proximal to the splenic flexure (extensive colitis), often involving the entire colon (pancolitis or universal colitis).

On occasion, a so-called cecal patch of periappendiceal inflammation is encountered. This does not represent a true skip lesion suggestive of Crohn disease. Similarly, limited ileal involvement (backwash ileitis) can be seen in patients with ulcerative colitis who have pancolonic disease. Deep ileal ulcers, long segments of ileal involvement, or stricturing disease are consistent with Crohn disease and not ulcerative colitis. Although confluent disease involving the rectum is the rule in ulcerative colitis, patients on medical therapy, particularly topical therapy, may have apparent skip lesions or rectal sparing. This should be recognized as a treatment effect and not a manifestation of Crohn disease.

Unlike Crohn disease, ulcerative colitis is frequently acute or subacute in onset. Like Crohn disease, the subsequent clinical course is one of recurring episodes of symptomatic disease interspersed with episodes of relative (or complete) quiescence.

1. Symptoms and signs

As with Crohn disease, the symptoms of ulcerative colitis depend on the extent and severity of inflammation. Overt rectal bleeding and tenesmus are virtually universally present and may be the only symptoms in patients with proctitis alone. When the proximal colon is involved, diarrhea and abdominal pain are more frequent complaints. Nausea and weight loss portend more severe disease. Severe abdominal pain or fever suggests fulminant colitis or toxic megacolon.

Signs of ulcerative colitis include mild abdominal tenderness, often most localized in the hypogastrium or left lower quadrant. Digital rectal examination may disclose visible red blood. As with Crohn disease, signs of malnutrition may be evident. Severe tenderness, fever, or tachycardia heralds fulminant disease.

2. Laboratory findings

Patients with active disease are generally anemic and often iron deficient. Hypoalbuminemia suggests extensive disease with subsequent colonic protein losses. Leukocytosis, thrombocytosis, ESR, and CRP are nonspecific markers of systemic inflammation. Elevations in ESR and CRP are less common in ulcerative colitis than in Crohn disease.

Stool studies should be sent and found negative for typical bacterial pathogens, C difficile, and ova and parasites. Common positive findings in ulcerative colitis include fecal leukocytes and fecal lactoferrin.

Serologic markers have also been studied for ulcerative colitis. P-ANCA is the most commonly associated marker. However, as previously mentioned, it is also present in Crohn colitis, which limits its ability to distinguish the two conditions. As with markers in Crohn disease, P-ANCA may be helpful in predicting disease activity. Studies have suggested that P-ANCA-associated ulcerative colitis is more likely to be medically refractory, require early surgery, and result in chronic pouchitis in patients who have undergone ileal pouch anal anastomosis (IPAA).

3. Imaging studies

Plain films of the abdomen are useful predominantly in patients with symptoms of severe or fulminant colitis. So-called thumbprinting or thickening of the colon wall indicates severe colitis with bowel wall edema. With toxic megacolon, the bowel is dilated with loss of haustral markings. Intestinal pneumatosis is a late finding and signals bowel ischemia and infarction. Obstructive findings are less common in ulcerative colitis than in Crohn disease and usually suggest malignancy. Barium enema is less commonly used since the advent of flexible sigmoidoscopy and colonoscopy. Nonetheless, it can be useful for detecting active ulcerative disease, polyps, or masses. In ulcerative colitis, the colon typically appears granular and shortened, perhaps as a consequence of chronic inflammation or fibrosis. Pouchography (contrast study of the pouch) in patients who have undergone IPAA permits assessment of diseases related to this operation, including leaks, pouchitis, fistulae, or strictures.

CT of the abdomen typically reveals colonic wall thickening, as with other forms of colitis (see Figure 9–21). Small bowel disease is not present, other than perhaps mild ileal inflammatory changes. Once a diagnosis of ulcerative colitis has been made, CT has only a limited role as an imaging modality, because endoscopic examination is typically the preferred modality for disease assessment.

Colonoscopy allows assessment of the extent of disease and severity of involvement. Classic findings include confluent inflammation extending proximally from the anal verge, with mucosal erythema, edema, and granularity and loss of normal vasculature. With more severe disease, the mucosa becomes overtly hemorrhagic, with ulcerations and a purulent exudate. So-called backwash ileitis, characterized by mild terminal ileal erythema, is seen in patients who have pancolitis. Pseudopolyps are commonly encountered in patients with long-standing disease. These are polypoid nondysplastic colonic lesions of hypertrophied tissue, often with surrounding atrophic mucosa. They are thought to represent the sequelae of chronic recurrent inflammation and healing, and harbor no malignant potential. Dysplastic or frankly malignant polyps or mass lesions are also encountered at higher rates in patients with ulcerative colitis. These lesions are discussed in more detail under Complications, below. Both pseudopolyps and colitis-associated neoplastic lesions are also seen in patients with Crohn disease.

Flexible sigmoidoscopy is a useful tool for disease assessment in the setting of flares of colitis. In this setting, a full colonoscopy is typically overly cumbersome for the patient and may carry an undue risk of perforation in patients with severe colitis. Flexible colonoscopy can assist with assessment of disease severity and help to exclude alternative diagnoses, such as infectious or ischemic colitis.

C. Diagnostic Considerations

No single symptom, physical finding, or test result can diagnose IBD. The diagnosis of both Crohn disease and ulcerative colitis is a clinical one, based on compatible patient history; physical examination; and laboratory, radiographic, endoscopic, and histologic findings. Diagnostic tools have been discussed at length in the preceding sections. A detailed discussion of the histologic findings of IBD is beyond the scope of this chapter. Noncaseating granulomas and transmural disease both are highly specific to Crohn disease. Colonic biopsies in both ulcerative colitis and Crohn colitis demonstrate evidence of acute inflammation, characterized by neutrophilic cryptitis, and chronic inflammation, such as crypt distortion and a plasmacytic infiltration of the lamina propria. A skilled pathologist is indispensable in helping to characterize the histologic findings and make the diagnosis of IBD.

For both the initial diagnosis and subsequent flares, other conditions that mimic IBD should be excluded (see next section). Of particular importance is the exclusion of infectious pathogens, as the treatment of active IBD frequently involves immunosuppressive medications. For patients who do not respond to medical therapy (or worsen despite it), the diagnosis of IBD should be rechallenged.