Although many investigators have sought an infectious agent in CD, there has never been any conclusive evidence that such an agent will ever be isolated. For many years, there has been speculation that the immune system may be involved in the pathogenesis of the disease.

UC may be caused by a transmissible agent that results in a theoretic immunologic response in the colon, although nobody has been able to elucidate a possible agent. Patients with UC also have a defect in the protective mucous glycoprotein secretion that is not present in patients with CD (3).

In reported series of CD patients, the percentage of people with a family history is 10% to 20% (4). The proband concordance rate among monozygous twins is 54% for CD. Heredity may be quite strong in those who develop CD before early adulthood. The hereditary link is much stronger in UC. More recently, much attention has been focused on splitting CD back into subgroups defined by clinical features such as anatomic location of disease, extent of disease, and disease behavior (i.e., inflammatory, fistulizing, or fibrostenotic). High concordance rates for anatomic location of CD and disease behavior have been reported in CD-affected relatives, suggesting that these clinical features may be genetically determined (5).

CD is common in northwestern Europe and North America. Low prevalence rates are reported in Hispanics and Asians. Areas of low incidence include Japan and southern Europe. CD is infrequent in South America, Asia, and tropical Africa.

The hallmark of CD is its segmental distribution in the terminal ileum, often with rectal sparing but frequently with perianal disease. The transmural nature of the inflammatory process is characterized by deep fissures that penetrate adjacent structures, causing abscesses and fistulas. Fat wrapping of involved bowel segments and mesenteric lymphadenopathy are common stigmata. The principal microscopic features are noncaseating granulomas with multinucleate giant cells, microabscesses, fissures, a chronic inflammatory cell infiltrate, lymphoid hyperplasia, edema, and fibrosis. Identification of noncaseating granulomas is possible in 70% of patients; in the remaining 30%, the diagnosis is made by a combination of overall gross and microscopic features.

Unlike CD, UC is a continuous disease, maximally involving the rectum and spreading proximally. There are no true skip lesions; the involved segment in UC is contagious; and areas that may appear normal on endoscopic examination are always abnormal when examined microscopically. In 10% to 20% of patients with pancolitis, the ileum is also involved in a process that is indistinguishable from the colonic disease for 5 to 15 cm. UC is predominantly a mucosal disease characterized by epithelial ulceration and regeneration. In active disease, polymorphonuclear infiltration with crypt abscesses is the hallmark of the disease. Depletion of the goblet cell mucin is characteristic, and its extent is related to the severity of the disease.

The features characteristic of CD in the large intestine are rectal sparing; distal ileal involvement; focal aphthous ulcers; deep ulceration with a cobblestone pattern; and fistula, abscess, or stricture. In contrast, UC produces intermittent attacks of rectal bleeding in combination with granular mucosal disease.

CD, unlike UC, rarely goes into complete remission. Once the disease becomes symptomatic, it tends to progress to its hallmark complications of obstruction, local sepsis, and fistulas. Patients with inactive disease may develop the mechanical complications but not usually sepsis, and the course of the disease is relatively benign. Active disease is associated with florid and diffuse small-bowel disease or active colitis that has associated metabolic sequelae and sepsis.

The survival rate in patients with CD does not differ from that of the general population. Chronic active small-bowel disease tends to progress toward obstruction. The most common presentation of colonic disease is diarrhea and weight loss. Anorectal strictures tend to be progressive and may eventually require proctectomy. Anorectal fistulas have a variable course. Recurrence of CD is almost inevitable, and recurrent disease tends to have the same presentation as the original episode. Recurrence is more common in perforating disease than in nonperforating (i.e., obstruction, bleeding) disease.

CD is usually demonstrated by the use of contrast radiographs. The diagnosis of small-bowel disease is best demonstrated either by upper gastrointestinal contrast study with modified follow-through examinations or by use of enteroclysis studies. The classic string sign is usually from edema and spasm rather than fibrosis. Colonic disease can be demonstrated by double contrast studies. The general radiologic features can be best summarized as edema, ulceration, fibrosis, and fistulas. Fistulas are more common in small-bowel than in large-bowel disease. Traditionally, colonic CD affects the proximal colon, usually with ileal involvement. Approximately 50% of patients with CD have rectal disease. The coalescence of ulcerated areas leads to the formation of the cobblestone pattern. The terminal ileum is involved in 50% to 70% of patients with Crohn’s colitis. Strictures in CD tend to have tapered margins in contrast with carcinomas, which have abrupt narrowing.

Plain radiographs can be useful in patients with acute fulminant colitis, in whom the affected segments of the colon are widened and distended with air. Toxic megacolon usually affects the transverse colon, but it also may involve the sigmoid colon. Contrast radiology should never be used in patients with acute colitis because of concerns about septicemia, perforation, and megacolon. The earliest radiographic changes are an irregular mucosal line that is thick and indistinct.

As the disease progresses, more severe superficial ulcerations or erosions appear. The presence and extent of ulceration correlates well with the disease activity. Eventually, the denuded mucosa is replaced by granulation tissue, leaving only islands of intact mucosa. These pseudopolyps are the result of severe colitis; they indicate an inflammatory process and virtually never become malignant. Although the rectum is usually the most involved structure, there is some relative rectal sparing in 20% of patients. Any stricture must be differentiated as benign or malignant.

Endoscopy shows the mucosal surface in CD as granular or nodular with friability, erosions, and aphthous ulcers. Discontinuous disease, especially with aphthous ulceration or serpiginous linear ulceration, is pathognomonic of Crohn’s colitis. Aphthous ulceration is believed to be the first macroscopically recognizable sign of CD. Deep linear ulcers give rise to a cobblestone pattern. True cobblestoning occurs only in patients with CD. As a general rule, cobblestoning, discontinuous disease, and anal lesions suggest CD.

Endoscopy is essential for obtaining biopsies and making the diagnosis of UC. The findings at endoscopy are usually more pronounced than can be seen radiographically.

No. Despite the differences outlined, in approximately 10% to 15% of cases there is doubt about diagnosis. Eventually, the patient’s history dictates the final diagnosis. Recurrence in the small bowel, perianal disease, fistulas, and abscesses are hallmarks of CD, regardless of what the original biopsies may have indicated.

Medical therapy is the first-line treatment in patients with uncomplicated CD. Corticosteroids have been beneficial for acute CD. Azathioprine and 6-mercaptopurine have a steroid-sparing effect that may require months before the effect can be noted. Cyclosporine also has been shown to be somewhat useful in maintaining remission. Metronidazole has been used extensively in patients with perianal disease and to a certain extent in those with left-sided colonic disease (8). Sulfasalazine has a limited role in Crohn’s colitis and no therapeutic benefit for ileal CD. It does not appear to have a corticosteroid-sparing effect. Adverse reactions to the sulfapyridine moiety of sulfasalazine occur in 15% of patients.

As with Crohn’s colonic disease, steroid therapy is initiated to control the disease, and as the steroids are reduced, sulfasalazine is added to prevent relapse. The active ingredient of sulfasalazine, 5-aminosalicylic acid, can be delivered orally or in enemas or suppositories. In contrast to CD, the immunosuppressive agents have not been shown to have singular benefit.

Sulfasalazine consists of sulfapyridine bound to 5-aminosalicylic acid. It was first used in 1942, and clinical benefit was demonstrated by 1948. Unfortunately, sulfasalazine may be associated with dose-related side effects such as nausea, vomiting, headache, and malaise. Side effects rarely occur when the dose is less than 4 g per day. Sulfasalazine crosses the placental barrier and can impede the absorption of albumin-bound drugs. Most of the side effects of sulfasalazine are due to the sulfapyridine fraction of the molecule; therefore, pharmacologic research has concentrated on removing that moiety. Maintenance therapy with sulfasalazine usually consists of 2 g per day.

Carry out metabolic surveillance in anyone with inflammatory bowel disease. Electrolyte and nutritional abnormalities are common and should be aggressively sought. Complete bowel rest by total parenteral nutrition has not been shown to reduce the colectomy rate or offer clinical benefit to patients with UC or CD. Nutritional support should be carried out, however, to allow for repair of the diseased bowel.

Studies on the clinical utility of monitoring thiopurine metabolites and preliminary investigations into the potential therapeutic role of 6-thioguanine have helped improve our understanding and use of azathioprine and 6-mercaptopurine. It appears that repetitive infliximab infusions may be used to maintain remission in CD, and every 8-week infliximab infusions do not result in increased side effects. Trials using other antibodies directed at tumor necrosis factor (TNF)-α have not shown the same clinical benefit as infliximab.