IBD—recognition, diagnosis, and therapeutics

Tom Colletti, MPAS, PA-C

Mr. Colletti is a Clinical Associate and Academic Coordinator at the Duke University Medical Center PA Program, Department of Community and Family Medicine, Durham, NC. The author has indicated no relationships to disclose relating to the content of this article.

An accurate diagnosis is crucial in managing ulcerative colitis and Crohn's disease; the clinical presentation and the use of endoscopy are essential to the evaluation of inflammatory bowel disease.

 

Earn Category I CME credit by reading this article and the associated article and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of May 2004.

Learning objectives Identify the factors implicated in the pathogenesis of inflammatory bowel disease (IBD) Describe the clinical presentation and the characteristics that differentiate ulcerative colitis from Crohn's disease Discuss the methods used, especially endoscopic imaging, to confirm the diagnosis of IBD Compare treatment choices for symptom control and surgical management

The term inflammatory bowel disease (IBD) encompasses two disorders, ulcerative colitis (UC) and Crohn's disease (CD). Although abdominal pain is common to both, other presenting signs and symptoms are different, as is the underlying pathology. Both disorders are marked by remissions and exacerbations. UC is limited to the colon, with lesions confined to the mucosa and submucosa, and the disease is characterized by continuous inflammation. CD involves the entire GI tract, with lesions extending through the intestinal wall to the serosa, and this disease is characterized by discontinuous inflammation.¹ The diagnoses of UC and CD require a careful history, physical examination, laboratory evaluation, and appropriate imaging studies. The PA's knowledge of the etiologies, epidemiology, clinical presentation, and endoscopic options available for evaluating the patient with abdominal pain and bloody diarrhea is essential in making the diagnosis of IBD.

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A complex etiology

Infection, diet, luminal flora, dysregulation of mucosal immune function, and environmental factors such as smoking have all been implicated in the etiology of IBD, although no specific causative factors have been definitively identified.² A genetic component has also been suggested because patients who have a first-degree relative with IBD have the greatest risk of developing the disease.² A modest association between HLA gene variants and IBD has been found in Japanese and Jewish populations.³ Recently, CD-associated NOD2 gene variants that alter the mucosal immune response to bacteria have been identified; NOD2 gene variants were identified in 17% of patients with CD compared to 5% of controls.⁴ Microbial factors may also have a role in the development of IBD (see Table 1).⁵ High intake of margarine, refined sugar, and animal fat has also been associated with an increased risk of CD.⁶

 

TABLE 1 How microbial factors may affect the development of IBD
Theory	Mechanism
Aberrant host immune response to normal luminal contents	Normal resident microflora, toxins, bacterial products, or food antigens upset the balance between proinflammatory and immunosuppressive forces, causing intestinal inflammation*
Altered enteric microflora components (dysbiosis)	Distinct adherent strains of Escherichia coli have been identified as a cause of intestinal inflammation in patients who have CD; these strains secrete enterotoxins and produce dysregulation of the mucosal immune system†
Specific pathogenic infection	High concentrations in the lumen of organisms such as Mycobacterium paratuberculosis, paramyxovirus, Listeria monocytogenes, and Helicobacter hepaticus predispose patients to developing IBD‡
Defective mucosal barrier to luminal antigens	An impaired intestinal mucosal barrier allows increased uptake of proinflammatory molecules and antitoxins, stimulating the development of chronic enterocolitis‡
* Mourelle M, Salas A, Guarner F, et al. Stimulation of transforming growth factor beta 1 by enteric bacteria in the pathogenesis of rat intestinal fibrosis. Gastroenterology. 1998;114:519-526. † Darfeuille-Michaud A, Neut C, Barnich N, et al. Presence of adherent Escherichia coli strains in ileal mucosa of patients with Crohn’s disease. Gastroenterology. 1998;115:1405-1413. ‡ Farrell RJ, LaMont JT. Microbial factors in inflammatory bowel disease. Gastroenterol Clin North Am. 2002;31:41-62.

Other factors appear to decrease the risk for developing UC. Patients who have undergone appendectomy are at reduced risk for the occurrence of UC.^7,8 The theory is that mucosal immune system alterations resulting from appendectomy affect the pathogenesis of UC. Smokers have a lower incidence of UC than nonsmokers, while those who have quit smoking have an increased risk of developing UC.¹ The protective effect of smoking has been shown to be significant enough to lead to positive therapeutic trials with the use of transdermal nicotine patches in UC.⁹ Conversely, smoking is associated with an increased risk of developing CD,¹⁰ suggesting two distinct mechanisms for these disorders.

The prevalence of CD in the United States and Canada is 26 to 198 cases per 100,000 population; of UC, it is 37 to 229 cases per 100,000.¹¹ The annual incidence of CD in North America is 9,000 to 44,000 new cases; for UC, it is 7,000 to 43,000 new cases.¹¹ An increased prevalence of IBD has been reported among Israeli Jews who have migrated to Europe and America.¹¹ No clear gender distribution has been identified for CD, although UC occurs slightly more often in men.¹² Most patients are in the third or fourth decade of life at the time of diagnosis, with a second smaller peak occurring among patients in the sixth or seventh decade. IBD in children accounts for 10% to 15% of cases.¹¹

Making the diagnosis

The differential diagnosis of IBD includes infectious, ischemic, and radiation colitis; diverticulitis; appendicitis; and neoplasm. Consider infectious colitis in patients who have had symptoms for fewer than 4 weeks and whose history of recent travel, diet, and antibiotic use suggest an infectious etiology. Stool culture and parasite examination should be performed to rule out enteric pathogens. Because IBD is associated with anemia and an increased erythrocyte sedimentation rate (ESR), a marker of inflammation, a laboratory evaluation including a CBC and ESR should be obtained.

Ischemic and radiation colitis manifest with a constellation of symptoms similar to that of IBD and are suggested by a history of atherosclerosis or radiation therapy, respectively. Clues to appendicitis, diverticulitis, and neoplasm include the location of pain and duration of symptoms.

Because IBD signs and symptoms are not pathognomonic, endoscopy has an important role in making the diagnosis (see Figure 1 and Figure 2). Endoscopy permits direct visualization of the mucosa and allows a biopsy specimen to be obtained for histopathologic study. Colonoscopy with biopsy is preferred for diagnosing suspected UC.¹³ Flexible sigmoidoscopy is generally the initial study obtained in patients presenting with acute symptoms of IBD and can help distinguish infectious colitis from IBD.¹⁴ Colonoscopy, however, is appropriate for patients with acute disease whose condition is stable.¹⁴

Click here to view full-size graphic

Click here to view full-size graphic

Upper GI disease is found in fewer than 5% of patients with CD,¹⁵ and although most of them have no GI symptoms, some may have pyrosis, dysphagia, or epigastric pain. In patients with these symptoms, gastroscopy with biopsy may reveal ulcerations, strictures, and normal mucosa next to inflamed mucosa—all findings that suggest CD. As many as 80% of patients who have CD have small bowel involvement.¹³ Small bowel studies are both diagnostic and essential in assessing the extent of disease. Advances in imaging technology allow visualization of the distal jejunum and ileum using the microcamera pill.¹⁶ CT is useful in assessing extramural manifestations, masses, abscesses, and fistulas in patients with IBD.

Presentation and treatment of ulcerative colitis

A patient who has UC generally complains of bloody diarrhea, crampy lower abdominal pain, fever, urgency, and fatigue. Weight loss and anemia are frequently noted in severe UC. Disease is confined to the rectosigmoid region in 50% of patients and to the left-sided colon in 30%; it extends more proximally in 20%.¹

Disease can be mild, moderate, or severe. In mild disease, patients have fewer than four stools daily, intermittent bleeding, with normal hematocrit and ESR levels. Moderate disease is characterized by four to six stools daily, frequent bleeding, a hematocrit of 20% to 30%, and an ESR of 20 to 30 mm/h. Severe disease is characterized by more than six bloody stools daily, a hematocrit of less than 30%, weight loss greater than 10%, and an ESR greater than 30 mm/h.¹⁴

Pathologic features of UC include friable and ulcerated colonic mucosa. Mucosal inflammation is superficial and is typically pronounced in the rectal mucosa, which is always involved in UC. Lesions are confined to the mucosa and submucosa, with inflammation seen in a sharply demarcated, continuous pattern.¹⁷ Histologic studies reveal significant infiltration of colonic crypts with neutrophils and increased lymphocytes. Long-standing inflammation is associated with epithelial cell dysplasia and an increased incidence of adenocarcinoma.¹⁷

First-line treatment for UC is a drug that contains 5-aminosalicyclic acid (5-ASA).¹⁸ Sulfasalazine (Azulfidine) is typically the first drug used because it is inexpensive, effectively controls mild and moderate disease, and induces remission in many patients.¹⁹ High dosages of sulfasalazine are often poorly tolerated, however, with many patients experiencing nausea, headache, hemolysis, and folate deficiency. Other 5-ASA agents, such as olsalazine (Dipentum), mesalamine (Asacol, Pentasa, Rowasa), and balsalazide (Colazal), have fewer side effects and may be used by patients who cannot tolerate sulfasalazine. These drugs are given either orally or rectally in an enema or suppository, depending on where the colon is inflamed.²⁰

Oral corticosteroids are often effective at reducing inflammation and symptoms of pain and diarrhea in moderate and severe disease. Oral prednisone achieves remission in 80% of patients who have moderate disease and in 47% of those who have severe disease.²¹ A corticosteroid may also be delivered in an enema suspension that is effective for distal disease. These drugs are associated with a high relapse rate, however, and do not effectively maintain remission.²² Switching to an immunomodulating agent, or surgical intervention, should be considered in patients who are dependent on corticosteroids to prevent the long-term effects of corticosteroid use, including osteoporosis and myopathy.

The immunomodulating drugs azathioprine (Imuran) and mercaptopurine (Purinethol) have an anti-inflammatory effect that suppresses T-cell and natural killer cell activity and hence can maintain remission. Blood counts should be obtained at least every 3 months to monitor for bone marrow suppression and leukopenia.²³ Immunomodulating agents can take as long as 4 months to work, however, delaying initiation of a corticosteroid taper.

Cyclosporine (Neoral, Sandimmune, SangCya) inhibits T-helper cells and has been shown to be beneficial in severe disease that does not respond to corticosteroids. Improvement is seen in a few days.⁶

Presentation and treatment of Crohn's disease

CD should be suspected in a patient who complains of an insidious onset of colicky abdominal pain that occurs before bowel movements and is relieved after passing stool. The terminal ileum is the most common site of inflammation in CD, causing right-side abdominal pain that can mimic acute appendicitis. A complaint of periumbilical pain suggests colonic or generalized small bowel disease. Diarrhea that may be bloody occurs in approximately 50% of patients who have CD.² Weight loss is noted in 85% of children at the time of diagnosis.⁶ Malabsorption results from anorexia (a common symptom of CD), abdominal pain, and diarrhea and is also a side effect of the drugs used to treat the disease. Because CD can manifest anywhere along the GI tract, anal fistulas or oral ulcers may be noted. Gastroduodenal disease may cause signs and symptoms of gastritis.

Medical therapy for CD depends on disease location and severity (see Table 2). The goal of treatment is to relieve acute symptoms and maintain remission. Regimens are tailored according to the patient's response to treatment.

 

TABLE 2 Measuring the severity of Crohn’s disease

Mild to moderate No dehydration or obstruction; weight loss <10% Moderate to severe Fever, anemia, weight loss >10% Severe or fulminant Fever, obstruction, abscess

Mild or moderate disease is usually treated first with sulfasalazine or mesalamine, although the antibiotic metronidazole (Flagyl, Protostat) is as effective as mesalamine in achieving remission.²⁴ Ciprofloxin is an acceptable alternative to metronidazole. Corticosteroids are also effective; controlled-release budesonide is associated with higher rates of remission than mesalamine.²⁵ Topical corticosteroids are useful in treating oral lesions.²⁶ Topical therapy consists of triamcinolone (Kenalog in orabase). Topical sucralfate may also be effective for local symptom relief. Symptomatic gastroduodenal disease may respond to a proton pump inhibitor.

Although corticosteroids are useful in moderate and severe disease, as maintenance therapy these drugs are neither safe nor effective.²⁴ Moderate or severe disease may respond to one of the immunomodulators, azathioprine or mercaptopurine. Methotrexate is an alternative agent that allows corticosteroid tapering to begin within 2 months of initiating methotrexate.²⁷ Infliximab (Remicade), a monoclonal antibody, has been effective in refractory disease, achieving remission in 33% of patients and inducing mucosal healing of CD lesions.²⁴ Reinfusion with infliximab every 8 weeks is needed to maintain its therapeutic benefit.

Severe or fulminant disease requires IV corticosteroids, and any abscesses should be drained surgically.²⁸ Drugs used to maintain remission include azathioprine, mercaptopurine, methotrexate, and infliximab.²⁴

Indications for surgery

Many of the complications of IBD, such as abscesses, fistulas, obstruction, and hemorrhage, require surgical intervention, and many patients who have UC undergo colectomy within 10 years of the original diagnosis. Up to 30% of patients who have IBD initially present with toxic colitis, with or without megacolon.²⁹ The incidence of toxic colitis in UC during the course of the disease is 10%.²⁹ Although toxic colitis was thought to be a rare complication of CD, studies have shown that it occurs in 50% of patients with the disease.³⁰

Toxic colitis requires treatment with electrolyte and fluid replenishment and broad-spectrum antibiotics.³⁰ Evidence of perforation, peritonitis, or hemorrhage warrants emergent surgery. Surgery may be considered to avoid perforation if no clinical response to medical management is seen within a 48- to 72-hour period.³⁰

Indicators for surgery in UC are intractable or fulminant disease, toxic megacolon, colon perforation, hemorrhage, and obstruction. Surgery is usually curative in UC once the inflamed section of colon is removed. Indications for surgery in the patient with CD include stricture and obstruction, hemorrhage, fistulas, and abscess formation. Surgery is rarely curative in CD because recurrence is common at the site of the anastomosis.²⁴

Extraintestinal manifestations

Extraintestinal manifestations occur in 21% to 36% of patients with IBD; any organ system may be involved.³¹ One theory for this occurrence is that dysregulation of the enteric immune system evokes autoimmune responses, leading to inflammatory processes in the extraintestinal sites.³¹

Eye, skin, joint, and mouth involvement may also occur in patients with CD in the colon. Nephrolithiasis, obstructive uropathy, malabsorption, and biliary stones occur mainly in patients with CD. Osteoporosis, hepatic disease and amyloidosis can also occur, with osteoporosis and osteopenia occurring in 23% to 59% of patients.³¹ Factors contributing to low bone mineral density include corticosteroid therapy, low levels of physical activity, inflammatory cytokines, small bowel resection, and vitamin D deficiency.

Cancer and IBD

Patients with UC have a 20- to 30-fold higher risk of developing colorectal cancer (CRC) than do those without UC.³² The longer a patient has UC, the higher the absolute risk of CRC; risk is 5% to 10% after 20 years of disease, and 30% after 35 years.³³ Because of this increased risk of CRC, surveillance colonoscopy with routine systematic colon biopsy is indicated. Some organizations also recommend CRC surveillance for patients with CD.

Colonoscopy should be initiated 8 to 10 years after the diagnosis of pancolitis is made but can be delayed if colitis is limited to the descending colon. After 10 years of disease, colonoscopy can be performed every 2 to 3 years; annual colonoscopy is recommended after 20 years of disease.³²

Conclusion

Patients presenting with chronic colicky abdominal pain, with or without bloody diarrhea, should be evaluated for IBD, along with appropriate stool studies to differentiate IBD from infectious colitis. Imaging studies including flexible sigmoidoscopy and colonoscopy with biopsy are important in making a definitive diagnosis. Numerous therapeutic options are available to treat acute symptoms, induce remission, and establish a maintenance regimen. Most patients with IBD will be managed in consultation with a gastroenterologist.

 

KEY POINTS in this article Ulcerative colitis is characterized by bloody diarrhea, lower abdominal pain, and urgency; Crohn's disease causes colicky abdominal pain, anorexia, and weight loss. Complications of IBD include toxic megacolon, abscess and fistula formation, colon perforation, and obstruction. Treatment for acute IBD includes sulfasalazine and other 5-aminosalicylic acid drugs, while corticosteroids and infliximab may be useful when disease is unresponsive to conventional treatment. Ulcerative colitis is associated with an increased risk of colorectal cancer, warranting surveillance colonoscopy and routine systematic colon biopsy for patients who have long-standing disease.

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Tom Colletti. IBD--Recognition, diagnosis, and therapeutics. JAAPA May 2004;17:16-24.

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