Approximately 25% of all new cases of inflammatory bowel disease occur in individuals younger than 20 years of age,1 making inflammatory bowel disease an important diagnostic consideration for the pediatrician and family physician. Although the clinical, radiographic, and endoscopic features of inflammatory bowel disease in children are usually sufficiently distinctive to permit a confident categorization of an individual case such as Crohn's disease or ulcerative colitis, about 15% of cases of colitis are classified as "indeterminate." The age of onset of inflammatory bowel disease is bimodal with peaks in the second and fifth decades of life.2
The precise pathogenesis of Crohn's disease and ulcerative colitis is unknown despite extensive attempts to identify infectious, genetic, and immunologie origins for both diseases. A positive family history is perhaps the greatest risk factor for inflammatory bowel disease.2 This is evidenced by the increased concordance in monozygotic versus dizygotic twins3 and a significant increase in relative risk in firstdegree relatives of an index case. Interestingly, there is an association between inflammatory bowel disease and syndromes such as Turner's syndrome, Hermansky-Pudlak's syndrome, and glycogen storage disease type Ib. The basis for these associations is uncertain. Recently, a putative Crohn's disease susceptibility locus on chromosome 16 has been identified.4 A search for genetic markers has shown an association between inflammatory bowel disease and class II alleles of the HLA complex on chromosome 6. Ulcerative colitis is associated with HLA-DR2,5 while Crohn's disease is associated with HLA-DR1, DQ5.6
For many years, investigators have debated whether inflammation in Crohn's disease and ulcerative colitis result from an appropriate immunologie response to an exogenous factor such as an infectious agent or from a dysregulated mucosal immune system causing an inappropriate immunologie response to normal luminal factors. The most recent evidence suggests the latter, ie, the mucosal immune system responds abnormally to normal luminal stimuli. Much has been learned from recently developed animal models. For example, 100% of interleukin-2-deficient mice that survive past 9 weeks of age develop a colitis that is similar clinically and histologically to ulcerative colitis in humans.7 An inflammatory bowel disease also develops in mice deficient in interleukin-108 and in T-cell receptor mutant mice.9 While it is doubtful that these are the specific abnormalities present in inflammatory bowel disease in humans, these models show that chronic mucosal inflammation can be the result of a primary immunoregulatory defect and that more than one immunologie pathway may be involved. They also suggest that despite different initiating mechanisms, the two conditions may have many downstream inflammatory processes in common.
PRESENTING FEATURES OF INFLAMMATORY BOWEL DISEASE
The presentation of ulcerative colitis varies in the extent of anatomic involvement and the presence or absence of extraintestinal manifestations. The majority of patients (50% to 60%) present with mildly bloody diarrhea and abdominal pain that may be difficult to differentiate from an infectious enteritis early in the disease course. A smaller percentage of patients have more severe symptoms including profuse bloody diarrhea, severe crampy abdominal pain with tenesmus, and urgency. A minority of patients will present with findings suggestive of a toxic megacolon, including bloody mucopurulent stools, fever, abdominal distension, obstruction, and tenderness. Patients may have no systemic symptoms or varying degrees of anorexia, weight loss, malaise, and low-grade or intermittent fever. Laboratory tests may reveal anemia, Ieukocytosis, and hypoalbuminemia in more severe cases. Ulcerative colitis may present with extraintestinal manifestations but this is more commonly the case in Crohn's disease,10 as discussed below.
The presentation of Crohn's disease also is determined primarily by the location and extent of disease involvement. Whereas the mucosal involvement in ulcerative colitis is limited to the colon, any portion of the gastrointestinal tract may be involved in Crohn's disease, accounting for a greater variability in presentation. Crohn's disease involving the small intestine usually presents with evidence of malabsorption including diarrhea, abdominal pain, growth deceleration, weight loss, and anorexia. Initially, these symptoms may be quite subtle, and any one may predominate the clinical picture. Small bowel mucosal disease may result in malabsorption of iron, zinc, or folate, or vitamin B12 deficiency.
Crohn's disease involving the colon may be clinically indistinguishable from ulcerative colitis with symptoms of bloody mucopurulent diarrhea, crampy abdominal pain, and urgency to defecate. Symptoms of painful defecation, bright red rectal bleeding, and perirectal pain may signal perianal disease, which may occur without symptomatic involvement in any other area of the intestinal tract. Perianal involvement includes simple skin tags, fissures, abscesses, and fistulae. Crohn's disease may present with extraintestinal manifestations with subtle or no gastrointestinal symptoms. The perineum should be inspected in all patients presenting with signs and symptoms of Crohn's disease because abnormalities detectable in this region will substantially increase the clinical suspicion of inflammatory bowel disease. In our experience, patients may have been referred to endocrinologists for assessment of short stature and delayed pubertal maturation, orthopedists or rheumatologists for evaluation of arthritis, or psychiatrists for evaluation of anorexia nervosa.11
The diagnosis of both Crohn's disease and ulcerative colitis is based on clinical presentation, laboratory evaluation, endoscopie appearance and histology of the mucosa, radiologìe findings, and exclusion of alternative etiologies. In a patient with suggestive signs and symptoms, laboratory findings may be helpfill in determining the extent to which more expensive radiographie and endoscopie tests should be done. Laboratory findings are not specific for either Crohn's disease or ulcerative colitis, but the presence of anemia, Ieukocytosis, an elevated erythrocyte sedimentation rate, and low serum total protein and albumin levels suggests inflammatory bowel disease and indicates the necessity for additional evaluation. The urinalysis is usually normal, but occasionally may reveal hematuria or pyuria.
Fresh stool samples should be examined for blood, leukocytes, and parasites and cultured for infectious pathogens such as Salmonella, Sfuggilo, Campylobacter, Yersinia, and Escherichia coti 0157:H7- Increased recognition of the latter pathogen as a common cause of bloody diarrhea, often in an afebrile patient, mandates that it be tested for in all stool cultures. In selected cases, serological titers may be necessary to exclude the parasite Entamoeba histolytica. Assay for Clostridium difficile toxin should be obtained in all patients regardless of prior antibiotic treatment. Interestingly, patients with ulcerative colitis appear to be at an increased risk for development of C difficile enterocolitis. The presence of a bacterial pathogen does not exclude the existence of underlying inflammatory bowel disease but does mandate specific therapy.10,11
Colonoscopy with mucosal biopsy of the colon and terminal ileum is the most sensitive and specific test for inflammatory bowel disease. Endoscopie access to the ileum is technically feasible in most children; thus, pancolonoscopy and ileoscopy is the diagnostic procedure of choice in the majority of patients presenting with signs and symptoms of inflammatory bowel disease. Extensive colonoscopic examination is contraindicated in patients with severe colitis because of the risks of perforation and hemorrhage, but this procedure can be performed safely in the majority of cases.
In Crohn's colitis, disease tends to be more active in the proximal colon and cecum, although pancolitis is not uncommon. There are usually intervening areas ("skip areas") that are normal both grossly and histologically. In ulcerative colitis, disease is uniformly more severe distally and extends proximally in a continuous manner. In both Crohn's disease and ulcerative colitis, biopsies may show nonspecific chronic inflammation even in areas with normal gross endoscopic appearance. When upper gastrointestinal tract involvement is suspected in Crohn's disease, endoscopy to explore the esophagus, stomach, and duodenum is indicated.
The primary role of radiologie evaluation is in defining disease of the small bowel. This usually can be accomplished wich an upper gastrointestinal series with small bowel follow through, although specialized techniques such as enteroclysis may be required occasionally. The terminal ileum is the most commonly involved site in Crohn's disease. Terminal ileal nodularity is a common finding, and this must be differentiated from lymphonodular hyperplasia, which is commonly seen in the pediatrie age group. Irregular, nodular, and thickened bowel loops, stenotic areas, deep ulcers, and fistulas also may be present. Barium contrast enema studies usually are not necessary.
The histologie appearance of mucosal biopsies usually permits differentiation of ulcerative colitis from Crohn's disease. In approximately 15% of colitis cases, however, there is some overlap in the findings, and a diagnosis of indeterminate colitis is made. By definition, inflammation in ulcerative colitis is limited to the colon. "Backwash ileitis" may occur but generally is not associated with clinical small bowel disease. Typically, the histologie appearance in ulcerative colitis is that of continuous acute and chronic inflammation. Crypt distortion and branching with mucin depletion are characteristics of chronic colitis. In Crohn's disease, there are discrete areas of inflammation with intervening normal regions. The inflammation is transmural and may be focal with adjacent areas of histologically normal mucosa. Noncaseating granulomas may be found in up to 50% of patients, and when present with transmurai inflammation, provide the strongest support for the diagnosis.10,11 In our experience, however, granulomas are quite uncommon.
Crohn's disease often presents a diagnostic challenge because of the highly variable and often subtle manner in which it is expressed clinically. The Table outlines the differential diagnosis based on the segment of bowel involved. The primary differential diagnosis in ulcerative colitis is enteric infection as discussed above. Early in the disease course, it may be difficult to differentiate acute infectious colitis from inflammatory bowel disease. Chronic changes in mucosal biopsies suggest ulcerative colitis. However, histologie findings of acute bacterial gastroenteritis may be associated with or trigger the first episode of inflammatory bowel disease, further complicating early diagnosis.10,11 Longitudinal observation and, in some instances, a follow-up sigmoidoscopy with biopsy are necessary in acute cases that persist beyond the expected interval of time.
Twenty-five percent to 35% of patients with inflammatory bowel disease have at least one extraintestinal manifestation. These may occur before the onset of gastrointestinal symptoms, during disease, or even after cotectomy in ulcerative colitis. The presence of extraintestinal manifestations may carry prognostic significance. For example, patients with ulcerative colitis and extraintestinal manifestations have a significantly higher rate of pouchitis following colectomy and ileal pouch-anal anastomosis.12
Erythema nodosum and pyoderma gangrenosum are two well-described skin manifestations of inflammatory bowel disease. Erythema nodosum is more common in Crohn's disease, affecting approximately 3% of patients. It has been estimated that 75% of subjects with erythema nodosum ultimately develop arthritis. Therapy involves treating the underlying bowel disease. Pyoderma gangrenosum is unusual, affecting less than 1% of patients with ulcerative colitis and even fewer patients with Crohn's disease. Pyoderma also is associated with arthritis. Medical therapy for the underlying bowel disease is not always successful. Intra-lesional therapy with steroids is useful occasionally, and colectomy results in healing in approximately one half of cases.12
Differential Diagnosis of Presenting Symptoms of Crohn's Disease*
The association of joint inflammation and inflammatory bowel disease is well known. In addition to the dermatologie conditions noted earlier, arthritis is associated with ocular inflammation. Peripheral joint involvement affects approximately 10% of patients and includes arthritis of the knees, ankles, hips, wrists, elbows, and interphalangeal joints in decreasing order of frequency. Treatment of peripheral arthritis typically involves treating the underlying bowel inflammation. Ankylosing spondyhtis occurs more rarely, affecting 1% to 2% of patients. While not truly an arthritis, clubbing is common in children with inflammatory bowel disease, particularly Crohn's disease involving the small bowel.12
Ophthalmologic manifestations may or may not reflect underlying bowel activity. Patients most likely affected are those with Crohn's disease involving the small bowel. A wide array of conditions may be seen, including episcleritis, uveitis, marginal keratitis, conjunctivitis, scleritis, orbital pseudotumor/myositis, optic neuritis, ischemie optic neuropathy, and retinal vasculitis. In addition, increased intraocular pressure may be seen in children receiving chronic systemic corticosteroid therapy. High daily dose schedules for an extended period are a significant risk factor. All patients with inflammatory bowel disease require ophthalmologic examinations at regular intervals.12
Aphthous stomatitis is the most frequent oral manifestation and occurs more commonly in Crohn's disease than ulcerative colitis. Oral lesions appear to parallel intestinal disease in most cases but also may antedate gastrointestinal symptoms.12
Multiple liver and biliary tract extraintestinal manifestations have been described. These include small and large bile duct inflammation, chronic active hepatitis, drug-induced hepatitis, granulomatous hepatitis, cirrhosis, bile duct carcinoma, fatty liver, amyloidosis, hepatic abscess, and cholelithiasis. Primary sclerosing cholangitis is perhaps the most well-known hepatobiliary complication. While the true incidence in children is not well known, one group documented sclerosing cholangitis in 3% of 180 children and adolescents in whom routine screening of serum transaminases was performed. The majority of these patients with primary sclerosing cholangitis had no hepatobiliary symptoms at the time of diagnosis but were detected by elevation of serum transaminases and *y-glutamyl transpeptidase. Long-term follow-up data in children are lacking; however, it does not appear that a large percentage develop significant chronic hepatobiliary complications.12
Cholelithiasis is a well-defined extraintestinal manifestation of Crohn's disease occurring most commonly in patients with terminal ileal involvement or who have had ileal resection. Because the terminal ileum is the site of bile acid reabsorption, increased fecal bile acid loss results in lithogenic bile and cholesterol stones. Patients with ulcerative colitis also have an increased risk of gallstones but the pathophysiology is not as well defined, except that perhaps the proximal colon plays a role in enterohepatic circulation.12
Nephrolithiasis is a relatively common renal complication of inflammatory bowel disease and can occur via several different mechanisms. In the presence of fat malabsorption, which occurs particularly with small bowel disease in Crohn's disease, dietary calcium binds to malabsorbed fatty acids in the colonie lumen and free oxalate is absorbed. This results in hyperoxaíuria and oxalate stones. In patients with an ileostomy, increased ostomy fluid and electrolyte losses may lead to a concentrated, acidic urine and the formation of uric acid stones.12
Other extraintestinal manifestations include pancreatitis, fibrosing alveolitis, interstitial pneumonitis, pericarditis, and peripheral neuropathy. Pancreatitis may result from 5-aminosalicylic acid preparations, 6mercaptopurine, and sulfasalazine therapy while peripheral neuropathy may occur with prolonged metronidazole therapy.
GROWTH FAILURE IN PEDlATRlC INFLAMMATORY BOWEL DISEASE
Growth failure is a common complication of inflammatory bowel disease in children and may be the presenting symptom.13 Figure 1 shows the growth chart of an adolescent girl who was referred to the pediatrie endocrinology clinic for evaluation of growth deceleration. She was asymptomatic. Her physical examination was normal except for a guaiacpositive stool and the growth curve as shown. The hematocrit was 32% and an erythrocyte sedimentation rate was 27 mm/hr. All other biochemical tests were normal, and she was referred to the pediatrie gastroenterology clinic for further evaluation. An upper gastrointestinal series with small bowel follow through was normal. Colonoscopy revealed aphthous lesions (Figure 2), and biopsy findings were characteristic for Crohn's disease. Her growth rate improved with therapy, and she has demonstrated a normal progression into puberty. This case illustrates the subtle manner in which Crohn's disease may present.
Inadequate intake of nutrients is currently thought to be the primary factor in growth failure associated with Crohn's disease. Malabsorption appears to have little effect if the patient has not undergone bowel resection. Daily high-dose corticosteroid administration has been shown to be capable of suppressing growth; however, a recent prospective study suggests that it is the inflammatory process itself rather than corticosteroid use that causes growth failure.14 Children with inflammatory bowel disease should have their growth monitored closely and should receive aggressive nutritional intervention early on to allow maximal "catch-up" growth. Oral supplements may be used or in more severe cases, nocturnal nasogastric feeding may be beneficial. In addition, the use of alternate-day corticosteroids may he less growth suppressive.13
Figure 1. Growth curves for an 11 -year-old girl with Crohn's colitis. An 11 -year-old girl was referred to the pediatrie endocrinology clinic for evaluation of growth deceleration that occurred between the ages of 8 and 11 as shown in the growth curves. She was asymptomatic. Laboratory evaluation showed mild iron deficiency anemia and guaiac-positive stools, prompting referral to the gastroenterology clinic. Colonoscopy showed aphthous colitis as shown in the endoscopie photograph (Figure 2). There was no radiographie or endoscopie evidence of small intestinal disease activity. Subsequently, symptoms characteristic for Crohn's disease developed. Review of intermittent steroid therapy has resulted in improvement in growth. She has undergone normal pubertal development.
Figure 2. Endoscopie photographs from the patient described in Figure 1.
Conceptually, it is necessary to view treatment of inflammatory bowel disease as treatment of active dis' ease or treatment of disease in remission. The effectiveness of the rather broad armamentarium of drugs available for use is significantly dependent on whether the disease is active or in remission. For example, corticosteroids have impressive efficacy in active bowel disease, but no apparent benefit in maintaining a remission or prevention of complications due to relapse. In the discussion that follows, the reader should note the level of disease activity to fully appreciate the treatment required for pediatrie inflammatory bowel disease.
Corticosteroids induce a remission in most patients with active inflammatory bowel disease. They may be administered orally, parenterally, or rectally in the form of an enema or suppository. In patients with disease limited to the left colon, topical enema or suppository preparations may be used. For more extensive disease, therapy is initiated with daily administration of parenteral or oral prednisone or methylprednisolone. Following symptomatic improvement, the daily dose is slowly weaned over several weeks to an alternate-day dose. The goal is to ultimately discontinue use of corticosteroids because chronic use has no benefit after induction of remission. Significant side effects associated with chronic highdose use include masking of intraabdominal infection or perforation, adrenal suppression, diabetes, acne, facial pufnness, hirsutism, cutaneous striae, cataracts, glaucoma, aseptic necrosis of the hip, vertebral collapse, hypertension, and depression. The effect of steroids on growth is difficult to quantitate because active disease also has an adverse effect on growth and some patients assume normal growth velocity only after steroid treatment of active disease.15,16
These are the only agents with clear efficacy in maintenance of remission in inflammatory bowel disease. Major advances in the pharmacology of aminosalicylates have occurred in recent years. These advances primarily relate to the manner in which the drug is delivered in its active form into the intestinal tract. Sulfasalazine and 5-aminosalicylic acid (mesalamine) analogues are most commonly used to treat mildly or moderately active ulcerative colitis. Unlike corticosteroids, aminosalicylates are also useful in maintenance of a remission in ulcerative colitis, and some preparations are efficacious in maintaining remission in patients with Crohn's disease. They may be administered orally or topically in the form of an enema or suppository. Sulfasalazine is sulfapyridine linked by an azo bond to 5-aminosalicylic acid (5ASA), the active component that is released into the colonie lumen by bacterial reduction of the azo bond. Hence, sulfasalzine is only effective in colonie disease.
Sulfapyridine has no apparent therapeutic effect, but is responsible for the majority of side effects. The newer 5-aminosaHcylic acid compounds have been formulated without sulfapyridine to release active 5aminosalicylic acid in the small intestine and to reduce the frequency of side effects observed with sulfasalazine. Olsalazine consists of two 5-aminosalicyclic acid moieties which are hydrolyzed by bacteria and released in the colon. Mesalamine in eudragit-S is coated with a pH sensitive acrylic resin and is released at a pH >7 in the ileum. Mesalamine in microgranules coated with ethylcellulose releases 5aminosalicylic acid in the duodenum.17 These new formulations are the first drugs to have demonstrable benefit in maintaining remission in patients with small bowel Crohn's disease. Given the relatively high price of S-aminosalicylic acid preparations, sulfasalazine remains the initial agent of choice for children with mildly to moderately active ulcerative colitis. Coated mesalamine and olsalazine are alternatives for patients who cannot tolerate Sulfasalazine. Enema preparations may be used for left-sided colitis and suppositories for proctitis.
The most common adverse effects of Sulfasalazine are headache, malaise, and nausea. These usually respond to a reduction in dosage. Rarer but more severe side effects include severe hypersensitivity reactions, including skin eruptions, cholestasis or hepatitis, pancreatitis, pneumonia, hemolysis, and bone marrow toxicity. Sulfasalazine impairs folie acid absorption and a folate supplement should be administered. Hypersensitivity reactions, including pneumonias, pancreatitis, hepatitis, nephritis, and worsening of colitis, also have been reported with mesalamine. Nephrotoxicity has been rarely associated with 5-aminosalicylic acid compounds. Patients on either sulfasalazine or mesalamine should have routine blood counts and liver function tests. In addition, blood urea nitrogen, serum creatinine, and urinalyses should be obtained in patients on mesalamine.
Azathioprine and 6-Mercaptopurine
Azathioprine and 6-mercaptopurine are immunomodulatory agents with major efficacy in both Crohn's disease and ulcerative colitis. Azathioprine is metabolized in the liver to the active metabolite 6-mercaptopurine. Typically, these agents are used in patients with steroid-dependent or steroid-resistant inflammatory bowel disease. The average time to produce a clinical effect is 3 months, making them ineffective for acute management. Concern regarding the occurrence of malignancy in patients on long-term o-mercaptopurine therapy for inflammatory bowel disease has not been validated. In general, these agents are well-tolerated. Acute pancreatitis may occur within the first few weeks of therapy and usually resolves with discontinuation of the drug. Patients should be monitored at regular intervals for neutropenia, thrombocytopenia, anemia, and hepatic dysfunction. Parents should be alerted that appropriate cultures should be obtained and antibiotic therapy considered when a child has a fever or other signs of an infectious illness while on azathioprine or 6mercaptopurine.15,16
Cyclosporine and Other Investigational Drugs
Cyclosporine rapidly induces remission in most patients with severe ulcerative colitis. Efficacy also has been demonstrated in patients with active, severe Crohn's disease and fistulizing Crohn's disease. When used in high doses, however, the incidence of side effects is disturbing. In addition, the majority of patients relapse when the drug is withdrawn. Cyclosporine can be used to delay surgery in patients not psychologically ready or as a short-term interim measure while therapy with more slowly acting immunosuppressants such as 6-mercaptopurine is initiated.18
Exciting progress continues in the development of new agents for inflammatory bowel disease treatment. Patients should be appraised of the optimism for future meaningful developments. Promising preliminary studies have been published on the efficacy of methotrexate, antitumor necrosis factor a antibodies, budesonide (a locally acting steroid), and fish oil.
Broad-spectrum antibiotics are used to treat toxic megacolon and patients with intraabdominal abscesses. Metronidazole is useful in treating active Crohn's disease, especially perianal disease.15,16
Nutritional intervention can be used as primary or adjunctive therapy. Conflicting data exist on whether the administration of an elemental or polymeric diet is comparable with corticosteroid therapy in inducing remission in mild to moderate disease. Because elemental diets are unpalatable, nasogastric tube infusion often is required. Strict attention to nutrition support is required in children with established growth failure.15,16
Because ulcerative colitis is limited to the colon, colectomy is curative. A variety of anorectal pullthrough operations have been designed to permit gut continuity and avoidance of a permanent ostomy. In experienced centers, a minority of patients develop significant postoperative complications. About 15% of patients develop postoperative "pouchitis" and require intermittent antibiotic therapy and occasionally antiinflammatory therapy. The primary indications for colectomy in a group of 100 children with ulcerative colitis were published recently.19 The major factors leading to surgery were intractable disease (64%), refractory growth failure (14%), toxic megacolon (6%), hemorrhage (4%), perforation (3%), and cancer prophylaxis.
Inasmuch as Crohn's disease is a lifelong disease and may involve any area of the gastrointestinal tract, surgical options should be weighed carefully against the risks and benefits of ongoing medical therapy. Approximately 50% to 70% of children with Crohn's disease require surgery within 10 to 15 years of diagnosis. The indications for surgery are failure of medical therapy, obstruction, hemorrhage, perforation, fistula, growth retardation, carcinoma, and obstructive uropathy.
Patients with inflammatory bowel disease are at increased risk for gastrointestinal malignancy. It has long been known that patients who have had extensive ulcerative colitis for more than 10 years are at increased risk for colorectal cancer. It now appears that the risk for patients with longstanding Crohn's colitis may be similar.20 Patients with disease beginning in childhood and individuals with pancoUtis appear to have the greatest potential for malignancy. Management options include prophylactic colectomy or endoscopie surveillance for premalignant lesions.
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Differential Diagnosis of Presenting Symptoms of Crohn's Disease*