Diagnosis of Crohn's disease, as of ulcerative colitis, is made through the accumulation of history and physical findings, as well as laboratory, radiologic, endoscopic and histologic findings.

Initially, other causes of bowel inflammation must be excluded (Table 5). In the acute phase of Crohn's disease, viral gastroenteritis, appendicitis, Yersinia enterocolitis and Salmonella gastroenteritis must be excluded. If the Crohn's disease presents as a chronic recurrent illness, then culture of the stools and rectal mucosa for giardiasis, amebiasis, intestinal tuberculosis, nongranulomatous ulcerative jejunoileitis, fungal infections and pseudomembranous enterocolitis must be done. If the inflammatory state is limited to the colon or rectum, ulcerative colitis, ischemic colitis, diverticulitis, and occasionally cancer of the colon may simulate Crohn's disease.

A complete blood count (CBC) will reveal leukocytosis, an elevated erythrocyte sedimentation rate and thrombocytosis, all of which suggest that an active inflammatory process is present. Indices may be microcytic hypochromic if an iron deficiency anemia exists, macrocytic megaloblastic if a vitamin B₁₂ (absorbed in the terminal ileum) or folic acid deficiency exists. If both these states are present then the automated Coulter counter will present a normochromic, normocytic-type anemia that must then be investigated through peripheral smear and measurement of serum iron, total iron binding capacity (TIBC), ferritin, vitamin B₁₂ and folic acid levels.

Urinalysis may demonstrate a urinary tract infection if a fistula is present and proteinuria if amyloidosis has developed. The serum albumin is a useful indication of the patient's overall condition. It is low in those patients not eating, those with extensive malabsorption, and those whose disease is causing significant enteric loss of proteins. Serum alkaline phosphatase activity is frequently elevated in patients with Crohn's disease who have no other indication of liver disease. Serum carotene, calcium, phosphorous, Schilling test and stool fat assessment are useful in determining whether or not frank malabsorption is present. Lactose hydrogen breath test and ¹⁴C-labeled glycocholate breath test are useful in assessing the degree of lactose intolerance and bacterial overgrowth, respectively. Note that the ¹⁴C-labeled glycocholate breath test will also be abnormal in the presence of ileal disease or ileal resection.

Endoscopy, flexible sigmoidoscopy, and/or colonoscopy are useful for identifying and performing biopsies on discrete mucosal ulcerations. These ulcers vary in size and may appear round and punched out, serpiginous or linear. Often islands of normal mucosa protrude into the colonic lumen as a result of submucosal inflammation and edema. When prominent islands of mucosa are separated by linear ulcerations, the intestine assumes a cobblestone appearance. This pattern is characteristically different from that seen in ulcerative colitis, where diffuse ulceration extends without patches of normal mucosa.

The decision to perform colonoscopy should take into account the specific diagnosis and/or therapeutic issues that the procedure may be asked to resolve. These include (1) establishing a diagnosis; (2) activity of disease; (3) extent of involvement; (4) type of disease; and (5) suspicion of cancer.

The plain x-ray of the abdomen will reveal dilated bowel when a partial obstruction is present. Intra-abdominal masses resulting from matted inflamed loops of bowel or from abscesses can also be seen on the plain film.

An air contrast barium enema will demonstrate involvement of the colon and show narrowing, ulcerations, strictures or fistula formation. As with colonoscopy, a barium enema should be deferred in patients acutely ill with Crohn's colitis, since the examination is not critical for immediate management decisions and the risk of toxic megacolon and perforation is appreciable.

A barium enema may reveal disease of the terminal ileum as a result of reflux of barium past the ileocecal valve. However, determination of the extent of small bowel involvement requires administration of contrast medium orally or via enteroclysis. The small bowel abnormalities seen on x-ray are similar to those observed in the colon and include the characteristic cobblestone appearance, stenosis, and diseased segments separated by small bowel that appears normal (Figure 1).

It is important to note that changes in the appearance of both the large and small bowel on x-ray film correlate poorly with the course of the disease. There is thus no reason to take "routine" evaluative x-rays.

Mucosal biopsies obtained from the rectum, colon, terminal ileum or duodenum at the time of colonoscopy or upper endoscopy provide histologic documentation. Granulomatous inflammation of bowel mucosa strongly supports a diagnosis of Crohn's disease (Figure 2).

The management of Crohn's disease varies greatly depending upon the clinical status of the individual patient. No single therapeutic regime is considered routine for patients with Crohn's disease, and treatment must be individualized. 

When the patient presents with acute Crohn's disease, the history and physical examination are critical in determining the severity of the disease, in addition to gathering evidence of intestinal obstruction, bowel perforation or abscess. The use of steroids or immunosuppressive agents in the presence of gross infection is disastrous. In mild cases, diarrhea and abdominal cramps can be treated effectively with codeine, diphenoxylate (Lomotil^®) or loperamide (Imodium^®). In moderate or severe cases, the patient should be admitted to hospital, remain n.p.o. and be maintained with intravenous fluids. When symptoms and findings suggest small bowel obstruction, nasogastric suction is usually required until edema and spasm of the bowel subside. If evidence of abscess formation, fever and leukocytosis suggests a systemic infection, broad-spectrum antibiotic coverage should be initiated after appropriate cultures of blood, urine, fistulas or other possible sources of infection have been collected.

Symptomatic therapy may be necessary to control diarrhea in cases of chronic stable disease. As indicated above, diphenoxylate, loperamide and codeine are useful agents for controlling diarrhea, but they should be used carefully; they are potentially hazardous and should be promptly withdrawn if the patient's clinical status deteriorates.

Additionally, for patients with Crohn's disease, the diarrhea may be due to unabsorbed deconjugated bile acids that cause a cholerrheic diarrhea. Cholestyramine, an ion-exchange resin, effectively binds the unabsorbed bile salts and controls the diarrhea. Fat malabsorption may be treated with a low- fat diet supplemented with medium-chain triglycerides. Bacterial overgrowth proximal to areas of stenosis causes deconjugation of bile salts, again resulting in diarrhea; it responds well to courses of broad-spectrum antibiotics (e.g., tetracycline). Finally, lactase deficiency may occur secondary to the active inflammation and a trial of lactose-free diet is warranted.

The patient with Crohn's disease also requires continuous emotional support for this chronic, complicated illness; this support is necessary not only during acute attacks, but also during periods of remission. Although many consultants may be required to manage the varying aspects of complicated cases, one physician should be directly and continuously responsible for the overall care of the patient. Psychiatric consultation may occasionally be necessary for specific problems; however, successful management requires that continuous emotional support come from the physician who is directing the overall care of the patient.

Nutritional deficiencies are frequent with Crohn's disease and often result from inadequate food intake by patients who have "learned" that ingestion of food aggravates diarrhea and abdominal pain. In addition, several pathophysiologic mechanisms contribute to nutritional problems in patients with Crohn's disease (Table 3). Nutritional problems may be further aggravated by surgical resection of diseased intestine, which decreases absorptive surface area; this decrease may be sufficient to interfere with an adequate absorption of multiple nutrients. Of particular importance, because of the distal small bowel involvement, is the malabsorption of bile salts and vitamin B₁₂, both of which have receptors located solely in the distal ileum.

Whatever the combination of mechanisms responsible for the impaired absorption and nutritional deficiencies in Crohn's disease, the physician must be attuned to assessing nutritional parameters, including ideal body weight, anthropometrics, serum proteins, and serum vitamin and mineral levels. The consequences of nutritional disturbances are particularly serious in children with Crohn's disease. Delayed growth and sexual maturation can and do occur, and if they are not corrected prior to closure of the epiphysis, permanent shortness of stature will result. Adjunctive nutritional therapy is, as well, required by patients who are malnourished at the time of their Crohn's exacerbation or who are unable to ingest adequate calories because of their disease.

Increasingly, patients with extensive and complicated Crohn's disease are being treated partially or completely with enteral or parenteral nutritional programs as a means of "resting" the gut, allowing fistulas to heal, inducing a positive nitrogen balance, and even causing weight gain. Short-term remission is often achieved through the use of "bowel rest"; however, relapse rates are high within a few months of discontinuing therapy. Recently, Greenberg et al. have demonstrated that disease remission could be induced provided the patient received an adequate number of calories. Furthermore, it did not matter whether these calories were provided through oral intake, oral intake supplemented with enteral elemental feeding, or total parenteral nutrition.

Although a small percentage of patients with Crohn's disease enjoy prolonged symptom-free intervals when treatment is not required, the vast majority experience long periods of symptomatic active disease or frequent relapses that necessitate treatment of the disease with anti-inflammatory and immunosuppressive agents (Table 6). Evaluation of the efficacy of such agents is extremely difficult, given the fluctuating activity and unpredictable long-term course of Crohn's disease. Recently, randomized double-blind control studies have attempted to answer some of the questions relating to drug therapy.

1.8.3.1.1 Rectal corticosteroid preparations

Rectal instillation of steroid- containing preparations is useful when Crohn's disease involves the rectum and the sigmoid region. The topical application of steroids allows for rapid healing of the area and restoration of the rectum and sigmoid to their stool reservoir capacity and, therefore, often leads to fewer episodes of diarrhea.

1.8.3.1.2 Systemic corticosteroid preparations

Corticosteroids are beneficial in the management of acute exacerbations of small and large intestinal Crohn's disease, in which they induce remission of symptoms and decrease disease activity indices (7). Although steroids continue to be used by many practitioners on a chronic basis in the management of Crohn's disease, there is little evidence to support administration to prevent disease relapse. Steroid therapy for acute disease is best begun at prednisone 40 mg/day (outpatient oral treatment in mild cases or inpatient intravenous therapy in severe cases). As improvement occurs, parenteral therapy may be replaced by oral administration of a dosage that is gradually reduced by 5 mg/week to the minimum level needed to suppress signs of the inflammatory process (20 mg) and then by 2.5 mg/week; the ultimate goal is to end steroid therapy. Unfortunately, this objective cannot always be achieved, and many patients become symptomatic when the dose of prednisone is reduced below 5-10 mg/day. This "steroid dependence" occurs frequently, and the amount necessary for maintenance varies from patient to patient. If possible, patients requiring long-term steroid therapy should be weaned onto an alternate-day regime; alternatively, the immunosuppressive therapy will allow steroid withdrawal or a lowering of the steroid dose.

5-ASA products can be broadly divided into those with predominant therapeutic effect in the colon and those with therapeutic effect in both the small bowel and the colon (Table 7). In Crohn's colitis, colon-specific mesalamine is equally effective in mild to moderate disease. In Crohn's disease involving the small bowel, the mixed, slow-release and pH-dependent mesalamine (Pentasa^®) and the pH-dependent release mesalamine (Mesasal^TM) appear to be effective in reducing small intestinal inflammation. In addition, both these products have been shown to be effective in reducing the frequency of Crohn's disease relapse. When used for acute treatment the average daily dose of 5-ASA products is 4 g/day (except for Dipentum^®, which is 2 g/day). When used for maintenance therapy the average dose is 2 g/day (Dipentum^® 1 g/day) (8).

Immunosuppressive agents are reserved for steroid-dependent or steroid- resistant patients. When combined with steroids, azathioprine (150 mg/day), its active metabolite, 6-mercaptopurine (1.5 mg/kg/day), cyclosporine (7.5-15 mg/kg/day), and methotrexate (15-25 mg/day) are useful in cases of both ileal and colonic Crohn's disease. A large number of case reports and open studies have found that immunosuppressive agents will induce remission in steroid-resistant or steroid-dependent patients in approximately 60-70% of cases; nevertheless, the relapse rate is high once the immunosuppressive agent is withdrawn (9-11). Methotrexate and cyclosporine appear to work more quickly than 6-mercaptopurine and azathioprine. While cyclosporine can be effective in inducing disease remission, a recently completed Canadian multicenter trial demonstrated that cyclosporine (7.5 mg/kg/day) was no more effective than placebo in maintaining Crohn's disease in remission. An ongoing multicenter trial continues to examine the role of methotrexate in maintenance therapy for Crohn's disease.

Metronidazole (250 mg t.i.d.) is as effective as sulfasalazine in acute colonic disease if the patient has not received prior therapy, in patients whose disease does not respond to sulfasalazine, and in the treatment of perianal disease. Side effects include metallic taste, disulfiram-like effects with ingestion of alcohol, paresthesias and peripheral neuropathy. Most side effects are reversible upon withdrawal of the drugs; however, the peripheral neuropathy may persist.

In view of the high rate of recurrence of Crohn's disease following resection of diseased bowel, operative therapy should be reserved for complications of the disease or for those cases where the disease unequivocally fails to respond to optimal medical management. Complications requiring surgery are (1) chronic obstruction; (2) symptomatic abscess or fistula formation; (3) enterovesical fistulas; (4) free perforation; and (5) retarded physical or sexual development in children with Crohn's disease. Removal of the diseased segment(s) in a young child will normally allow the child to grow and mature normally until the Crohn's disease recurs. Patients should be forewarned that surgery is not curative but is necessary for the treatment of complications. Patients should also be warned about the common recurrence of Crohn's disease after resection of the small bowel or after colonic disease. The recurrence rate is 40% within 5 years, 60% within 10 years and 85% within 15 years.

No therapeutic agents have been proven useful for maintaining a remission in Crohn`s disease; therefore, once the active disease has been treated and controlled, there is no rationale for continuing medical therapy. Recently, evidence has become available to suggest that mesalamine (Pentasa^®, Mesasal^TM) may be effective in preventing Crohn's disease relapse in a subset of patients.

In the past few years, a number of basic research studies have investigated the nature of the inflammatory process involved in inflammatory bowel disease. As a result, it is now known that several mediators, such as prostaglandins, leukotrienes, cytokines and platelet-activating factor, are involved in the inflammation. There is increasing evidence that 5-lipoxygenase products (leukotrienes) play a key role in causing and perpetuating mucosal inflammation, while cyclooxygenase products (prostaglandins) may provide a mucosal protective function (12,13). It has been recently shown that eicosapentaenoic acid, a fatty acid obtainable from marine fish, is metabolized by the lipoxygenase pathway to a less inflammatory leukotriene (LTB₅). Dietary supplementation with 3 g/day of eicosapentaenoic acid for 6 weeks reduced the capacity of neutrophils to produce LTB₄, and in a small open study, inflammatory bowel disease patients showed significant decrease in neutrophil inflammation and improvement in symptoms and histological appearance of rectal mucosa (14). Blocking the synthesis of leukotrienes with selective 5-lipoxygenase inhibitors or blocking the leukotriene activity at the receptor level with leukotriene B₄-receptor antagonists is another new approach to therapy.

Our understanding of the immunological complexities in inflammatory bowel disease is growing. Immune modulators have been proposed as therapeutic agents for treatment of Crohn's disease. Indeed, interleukin-10 (an anti-inflammatory cytokine) when administered intravenously to a small number of patients in a pilot project significantly improved disease activity in patients who had otherwise failed all conventional management. Similarly, antibodies to tumor necrosis factor (TNFa) have also resulted in marked improvement in Crohn's disease in a limited number of patients. It is exciting to speculate that future advances in the management of inflammatory bowel disease will be found in immunomodulatory therapy.

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