eMedicine Specialties > Gastroenterology > Systemic Disease Jan 20, 2009

Crohn Disease
Author: George Y Wu, MD, PhD, Professor, Department of Medicine, Director, Hepatology Section, Herman Lopata Chair in Hepatitis Research, University of Connecticut School of Medicine Coauthor(s): Marcy L Coash, DO, Staff Physician, Department of Internal Medicine, University of Connecticut; Senthil Nachimuthu, MD, FACP, Fellow, Department of Internal Medicine, Heart and Vascular Institute, Tulane University School of Medicine Keywords Crohn disease, Crohn's disease, regional enteritis, granulomatous enteritis, regional ileitis, terminal ileitis, inflammatory bowel disease, IBD, ulcerative colitis, UC, ileitis, colitis, ileocolitis Introduction Background Crohn disease is an idiopathic, chronic, transmural inflammatory process of the bowel that often leads to fibrosis and obstructive symptoms, which can affect any part of the gastrointestinal (GI) tract from the mouth to the anus. This condition is believed to be the result of an imbalance between proinflammatory and antiinflammatory mediators. Most Crohn disease cases involve the small bowel, particularly the terminal ileum. The characteristic presentation of Crohn disease is abdominal pain and diarrhea, which may be complicated by intestinal fistulization, obstruction, or both. Unpredictable flares and remissions characterize the long-term course of this illness. tract.4 Pathophysiology The exact cause of Crohn disease remains unknown. Current theories implicate the role of genetic, microbial, immunologic, environmental, dietary, vascular, and even psychosocial factors as potential causative agents. It has been suggested that patients have an inherited susceptibility for an aberrant immunologic response to one or more of these provoking factors.4 Microscopically, the initial lesion starts as a focal inflammatory infiltrate around the crypts, followed by ulceration of superficial mucosa. Later, inflammatory cells invade the deep mucosal layers and, in that process, begin to organize into noncaseating granulomas. The granulomas extend through all layers of the intestinal wall and into the mesentery and the regional lymph nodes. Neutrophil infiltration into the crypts forms crypt abscesses, leading to destruction of the crypt and atrophy of the colon. Chronic damage may be seen in the form of villous blunting in the small intestine as well. Ulcerations are common and are often seen on a background of normal mucosa. Although granuloma formation is pathognomonic of Crohn disease, its absence does not exclude the diagnosis.4 Macroscopically, the initial abnormality is hyperemia and edema of the involved mucosa. Later, discrete superficial ulcers form over lymphoid aggregates and are seen as red spots or mucosal depressions. These can become deep, serpiginous ulcers located transversely and longitudinally over an inflamed mucosa, giving the mucosa a cobblestone appearance. The lesions are often segmental, being separated by healthy areas, and are often referred to as skip lesions.4 Transmural inflammation results in thickening of the bowel wall and narrowing of the lumen. As Crohn disease progresses, it is complicated by obstruction or deep ulceration leading to fistulization by way of the sinus tracts penetrating the serosa, microperforation, abscess formation, adhesions, and malabsorption.1
1,2,3

In 1932, Crohn, Ginzberg, and Oppenheimer described this disease and noted its

localization to segments of the ileum. It was later noted that Crohn disease may involve any part of the GI

Obstruction is initially caused by significant edema of the mucosa and associated spasm of the bowel. Obstruction is intermittent and is often reversible with conservative measures and anti-inflammatory agents. With further disease progression, the obstruction becomes chronic because of scarring, luminal narrowing, and stricture formation.1 Fistulae may be enteroenteral, enterovesical, enterovaginal, or enterocutaneous. The inflammation extending through the bowel wall may also involve the mesentery and surrounding lymph nodes. Creeping fat may be seen when the mesentery wraps around the bowel surface.1 Serosal inflammation causes adhesions; thus, free perforations are less common in Crohn disease as in other inflammatory bowel conditions.1 Malabsorption occurs as a result of loss of functional mucosal absorptive surface. This phenomenon can lead to protein-calorie malnutrition, dehydration, and multiple nutrient deficiencies. Involvement of the terminal ileum may result in malabsorption of bile acids, which leads to steatorrhea, fat-soluble vitamin deficiency, and gallstone formation. Fat malabsorption, by trapping calcium, may result in increased oxalate excretion (normally complexed by calcium), causing kidney stone formation. 1 Nearly 30% of patients with either large- or small bowel disease develop perianal complications. Perianal complications may precede the development of intestinal symptoms and manifest as anal fissures, perianal fistulae, or abscesses.1 Although any area of the GI system may be affected, the most common site of Crohn disease is the ileocecal region, followed by the colon, the small intestine alone, the stomach (rarely), and the mouth. The esophagus is very rarely involved.1 In addition to local complications, a variety of extraintestinal manifestations may be associated with Crohn disease. The usual sites are the skin, joints, mouth, eyes, liver, and bile ducts. 5 Skin manifestations (eg, erythema nodosum, pyoderma gangrenosum, Sweet syndrome) and peripheral arthritis (eg, asymmetric involvement of larger joints) are probably more common with colitis than with enteritis. Aphthous ulcers are the most common mouth lesions. The more frequent nutritional-deficientcutaneous manifestation is acrodermatitis enteropathica due to zinc deficiency manifesting as psoriatic erythema.5 Ocular manifestations (eg, episcleritis, recurrent iritis, uveitis) are other manifestations of Crohn disease. These manifestations often parallel the course of bowel disease and usually subside when the disease is brought under control.5 Inflammatory arthropathies are the most common extraintestinal manifestations in patients with inflammatory bowel disease (IBD), with a prevalence between 7% and 25%. These are seronegative autoimmune-related disorders, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and sacroiliitis, which cause hip and back pain, may antedate the bowel disease by several years, and may persist after surgical or medical remission of the disease.
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Amyloidosis and thromboembolic manifestations may also occur. Compared with controls, patients with IBD have a 3-fold higher risk of thromboembolism, which is an important cause of morbidity and mortality. These patients have frequent exposure to classic thrombosis risk factors, including immobility, surgery, steroid therapy, and the presence of central venous catheters. Other factors that may play a role include smoking, antiphospholipid antibody syndrome, and hyperhomocysteinemia, which seem to occur more often in patients with IBD than in the general population.5

Urinary system involvement includes nephrolithiasis due to calcium oxalate stones. These are caused by

hyperoxaluria due to increased intestinal absorption of oxalate. Reports of renal amyloidosis have also been shown likely to be due to acute phase reaction proteins.
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Involvement of the liver varies from simple elevation of enzyme levels to benign pericholangitis, sclerosing cholangitis, autoimmune chronic active hepatitis, and cirrhosis. Cholelithiasis is more frequent in patients with IBD than in the general populationprobably due to bile salt pool alteration for malabsorption. Cholangiocarcinoma is a rare late complication of primary sclerosing cholangitis. Sometimes, a hepatic abscess manifests as fever of unexplained origin. Portal vein thrombosis and suppurative pylephlebitis have also been described.5 Frequency United States The prevalence of Crohn disease is approximately 7 cases per 100,000 population. The incidence and the prevalence of Crohn disease (especially the colonic subset) seem to have steadily increased over the last 5 decades, mainly in northern climates. International Incidence rates in Europe range from 0.7 to 9.8 cases per 100,000 persons. Rates in Asia range from 0.5 to 4.2 per 100,000. The lowest recorded rates of new cases appear to be in South Africa (0.3-2.6 per 100,000) and Latin America (0-0.03 per 100,000) respectively.1,2 The incidence and the prevalence of Crohn disease (especially colonic Crohn disease) seem to have steadily increased over the last 5 decades, mainly in northern climates. Distinct and reproducible geographic and temporal trends in incidence are observed. In both Europe and North America, higher incidence rates have been characterized in more northern latitudes.1,2 Urban areas may have a higher prevalence of inflammatory bowel disease (IBD) than rural areas. 1,2 Upper socioeconomic classes are thought to have a higher prevalence than lower socioeconomic classes, a fact likely influenced by increased access to health care, although genetic and environmental factors play a role.1,6 Mortality/Morbidity Crohn disease usually has a chronic, indolent course regardless of the site of involvement. Studies have estimated ranges from no increased risk to up to a 5-fold increased risk of death. Mortality appears to be the highest in the first 4-5 years after the diagnosis, and the 15-year survival rate is 93.7% of the general population. Over time, 10% of patients will be disabled by their disease.1 The chance of death and complications in Crohn disease increases with the duration of the illness. Patients with proximal small bowel disease have a higher risk of mortality compared with those who have ileal or ileocecal disease. The excess mortality may be ascribed to complications of Crohn disease.
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As the disease progresses, medical therapy becomes less effective. In the first year after diagnosis, the relapse rate approaches 50%, with 10% of patients having a chronic relapsing course. recurs after surgery.1 Race Data on the racial incidence of Crohn disease seem to show that the condition is uncommon in nonwhites in underdeveloped regions; however, this is not applicable to nonwhites in urban settings, where the rate may even exceed that of whites.1 Most patients develop complications that require surgery (approximately 80%). Crohn disease frequently

 Crohn disease is seemingly more common in whites than in blacks or Asians.1 A 2- to 4-fold increase in the prevalence of Crohn disease has been found among the Jewish population in the United States, Europe, and South Africa, as compared with other ethnic groups. Sex Studies throughout the world have shown a small excess risk of Crohn disease among women. Most reports show a female-to-male ratio between unity and 1.2:1.1 Age The age of onset of Crohn disease has a bimodal distribution. The first peak occurs between the ages of 15 and 30 years, and the second peak occurs between the ages of 60 and 80 years. However, most cases begin before age 30 years. A greater proportion of colonic and distal Crohn disease has been diagnosed in older patients, whereas younger patients have predominantly ileal disease.1 Clinical History Patients with Crohn disease most commonly present with symptoms related to a chronic inflammatory
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process involving the ileocolic region. o Low-grade fever, prolonged diarrhea with abdominal pain, weight loss, and generalized fatigability are usually reported. o The patients may develop crampy or steady right lower quadrant or periumbilical pain. The pain precedes and may be partially relieved by defecation. Diarrhea is usually nonbloody and often intermittent. o If the colon is involved, patients may report diffuse abdominal pain accompanied by mucus, blood, and pus in the stool.1,2,4,7,8 Patients with Crohn disease may also present with complaints that are suggestive of intestinal obstruction. o Initially, the obstruction is secondary to inflammatory edema and spasm of the bowel and manifests as postprandial bloating, cramping pains, and loud borborygmi. Once the bowel lumen becomes chronically narrowed, patients may complain of constipation and obstipation. Complete obstruction may sometimes be caused by impaction of undigested foods. o Perianal fissures or fistulae are common. o Cologastric fistulae may manifest as feculent vomiting, enterovesical fistulae as recurrent urinary tract infections and pneumaturia, enterovaginal fistulae as feculent vaginal discharge, and enterocutaneous fistulae as feculent soiling of the skin. o Development of fistulae into the mesentery may result in intra-abdominal or retroperitoneal abscess formation. o Patients may also have perianal disease, including perianal fissures, abscesses, and fistulae.
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Patients may have problems related to extraintestinal manifestations of Crohn disease, which may involve the skin, joints, mouth, eyes, liver, and bile ducts. Young people with Crohn disease commonly experience unexplained growth failure and delayed puberty. 1 Physical Physical examination should focus on the patient's temperature, weight, nutritional status, presence of abdominal tenderness or a mass, perianal and rectal examination findings, and extraintestinal manifestations. Tachycardia and pale mucosa can indicate acute anemia.

 Physical findings on abdominal examination may typically reveal abnormal bowel sounds, right lower quadrant tenderness (which is typical for ileal involvement), or a mass can sometimes be felt secondary to thickened or matted loops of inflamed bowel. Inspection of the perianal region can reveal skin tags, fistulae, abscesses, and scarring. A rectal examination can help determine sphincter tone and help detect gross abnormalities of the rectal mucosa or the presence of hematochezia. Examination of the skin and oral mucosa can be useful to reveal extraintestinal manifestations of the skin, including mucocutaneous ulcers, erythema nodosum, and pyoderma gangrenosum. Eye involvement is usually manifested as uveitis or episcleritis. A peripheral arthritis involving the large joints may also be present. Causes Genetic, environmental, microbial, immunologic, dietary, vascular, and psychosocial factors, including smoking, oral contraceptive, and nonsteroidal anti-inflammatory agents (NSAID) use, have been implicated in the pathogenesis of Crohn disease. Studies have shown compelling evidence for an inheritable risk for the development of Crohn disease. However, classic Mendelian inheritance is not seen. Most of the genes thought to be involved in the development of the disease play a role in mucosal immunity and are found on the mucosal barrier epithelium. 4 Several genes are thought to contribute to the complex phenotype; however, mutations within the NOD2 gene (or the IBD1 gene or CARD-15-caspase activating recruitment domain) have been shown to confer susceptibility to Crohn disease. Another region studied is the IBD-3 gene on chromosome 6 which is an area that includes the human leukocyte antigen (HLA) complex and has been linked with IBD. In addition, an area linked specifically to Crohn disease is on chromosome 5q, known as IBD-5, which contains a cytokine gene cluster.
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Environmental influences such as tobacco use seem to have an effect on Crohn disease. Smoking has been shown to double the risk, whereas in people who smoke, the risk of developing ulcerative colitis is less than in those who have never smoked.4 Infectious possibilities such as Mycobacterium paratuberculosis, Pseudomonas species, and Listeria species have all been implicated in the pathogenesis of Crohn disease, suggesting that the inflammation seen with the disease is the result of a dysfunctional but appropriate response to an infectious source. 4 Interleukins and tumor necrosis factor-alpha (TNF-alpha) have also been implicated in the disease process. Crohn disease is characterized by a T-helper type-1 cellular immune response pattern that leads to production of interleukin 12 (IL-12), TNF, and interferon gamma (IFN-gamma). TNF has been shown to play a critical role in the inflammation in this disease. Increased production of TNF by macrophages in patients with Crohn disease results in increased concentrations of TNF in the stool, blood, and mucosa. Differential Diagnoses Amebiasis Carcinoid Tumor, Intestinal Diverticulitis
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Other Problems to Be Considered Acute appendicitis Endometriosis (Yersinia enterocolitica)1 Ileocecal tuberculosis Systemic vasculitis Tubo-ovarian pathologies Workup Laboratory Studies Laboratory study findings in the evaluation of Crohn disease may indicate the presence of inflammatory activity or nutritional deficiencies. o Anemia may be due to multiple causes, including chronic inflammation, iron malabsorption, chronic blood loss, and malabsorption of vitamin B-12 or folate. o Leukocytosis may be due to chronic inflammation, abscess, or steroid treatment. o Hypoalbuminemia, hypocholesterolemia, hypocalcemia, hypomagnesemia, and hypoprothrombinemia may reflect malabsorption. o Acute inflammatory markers, such as C-reactive protein (CRP) and orosomucoid, correlate closely with disease activity. The erythrocyte sedimentation rate (ESR) is thought to be more helpful in assessing the disease activity of Crohn colitis than ileitis. o Stool samples should be tested for routine pathogens, ova, parasites, and Clostridium difficile toxin. These studies should also be checked to rule out infectious etiologies during relapses and before initiating immunosuppressive agents.6 Two serologic tests are available to attempt to differentiate ulcerative colitis from Crohn disease. o Perinuclear antineutrophil cytoplasmic antibody (p-ANCA), a myeloperoxidase antigen, is more commonly found in ulcerative colitis, whereas antibodies to the yeast Saccharomyces cerevisiae (ie, anti-S cerevisiae antibodies [ASCA]) are more commonly found in Crohn disease. o Therefore, a test result positive for p-ANCA antigen and negative for ASCA suggests the diagnosis of ulcerative colitis; conversely, a test result positive for ASCA and negative for p-ANCA antigen suggests the presence of Crohn disease. o However, these tests are only recommended as an adjunct to clinical diagnosis, as the test results are not specific and have been found to be positive in other bowel diseases. o Additional serologic markers such as Escherichia coli anti-ompC (outer membrane porin C) can be found in >50% of Crohn disease cases, and only a small percentage of ulcerative colitis case. Pseudomonas fluorescens (anti-12) may be found in >50% of Crohn disease cases and only 10% of ulcerative colitis cases. Flagellin-like antigen (anti-Cbir1) is associated independently with small bowel, intestinal penetrating, and fibrostenosing disease. These tests further increase sensitivity and diagnostic value. o These tests can provide prognostic information as well. Patients with Crohn disease whose condition is ASCA positive have a higher rate of surgery and require surgery earlier in the course of the disease, independent of the disease location.1,2,6 Imaging Studies Barium contrast studies o These studies are very useful in defining the nature, distribution, and severity of Crohn disease. An experienced radiologist should perform these studies to obtain the most information.

o An upper GI series, together with a small bowel follow-through (SBFT) and spot films of the terminal ileum, is the initial diagnostic procedure of choice in most patients who present with typical symptoms of Crohn disease. o SBFT can only indirectly detect alteration of the small bowel wall, and its sensitivity to detect marginal changes is low in comparison with direct inspection of the mucosa by endoscopy. o Once the patient can tolerate the procedure, barium enema may help in the evaluation of colonic lesions. Barium contrast studies are useful in evaluating features such as rigidity, pseudodiverticula, fistulization, and submucosal edema. These studies are noninvasive and usually well tolerated. In patients with ileitis, the terminal ileum may not be visualized, possibly because of spasming of the ileocecal valve. o Radiographic findings in both the small and large bowel parallel the clinical pattern. o Edema and ulceration of the mucosa in the small bowel may appear as thickening and distortion of valvulae conniventes. Edema of the deep layers of the bowel wall results in separation of the barium-filled bowel loops. o Tracking of deep ulcerations, both transversely and longitudinally, results in a cobblestone appearance. o Ileitis can also manifest as a string sign on barium study secondary to spasms or, rarely, because of fibrotic stricturing. o Fistulae can also be detected by barium studies of the digestive tract or through injection into the opening of the suspected fistulae.10,11,12 Computed tomography (CT) scanning is helpful in the assessment of extramural complications such as fistulae and abscesses, as well as hepatobiliary and renal complications. CT enterography can be helpful in the assessment of subtle mucosal damage.10,11,12 Magnetic resonance imaging (MRI) can be superior to CT scanning in demonstrating pelvic lesions. Because of differential water content, MRI can differentiate active inflammation from fibrosis, and it can distinguish between inflammatory and (fixed) fibrostenotic lesions in Crohn disease. 10,11,12 Ultrasonography is helpful in differentiating tubo-ovarian pathology. However, this modality can also detect enlarged lymph nodes, abscesses, stenoses, and even fistulae, and ultrasonography is regarded as a quick and inexpensive screening method to aid in the diagnosis of IBD or to repeatedly evaluate patients for complications.10,11,12 Rectal endoscopic ultrasonography has been used as an alternative to MRI in the assessment of perianal disease. This technique allows the differentiation of simple from complex fistulae, as well as the assessment of the tracts of the fistulae in relation to the sphincter muscle. 10,11,12 Radionucleotide scanning may be helpful in assessing the severity and extent of the disease in patients who are too ill to undergo colonoscopy or barium studies. Procedures Colonoscopy o Colonoscopy can be helpful when single-contrast barium enema has not been informative in evaluating a colonic lesion. o Colonoscopy is useful in obtaining biopsy tissue, which helps in the differentiation of other diseases, in the evaluation of mass lesions, and in the performance of cancer surveillance. o Colonoscopy also enables dilation of fibrotic strictures in patients with long-standing disease. Colonoscopy may also be used in the postoperative period to evaluate surgical anastomoses to predict the likelihood of clinical relapse as well as the response to postoperative therapy.1 Upper endoscopy
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o Upper endoscopy with biopsy is helpful in differentiating Crohn disease from peptic ulcer disease in patients with upper GI tract symptoms. o Endoscopic retrograde cholangiopancreatography (ERCP) is helpful both as a diagnostic procedure and a therapeutic tool in patients with sclerosing cholangitis and stricture formation. o Endoscopic ultrasonography (EUS) and magnetic resonance cholangiopancreatography (MRCP) may provide equally valuable information without invasive complications. o Double balloon endoscopy allows complete evaluation of the small bowel and makes distal ileal biopsies feasible. o Wireless capsule endoscopy helps to identify involvement of the upper GI tract which will occur in 40% of patients with Crohn disease. However, drawbacks include the inability to take biopsies, the risk of acute obstruction in stricturizing disease, and the time required for analysis. o Endoscopy can also be helpful in the detection of complications of Crohn disease. Magnifying endoscopy allows a more detailed view of the mucosal surface than conventional endoscopy. In combination with chromoendoscopy (indigo carmine), it is possible to further analyze the surface staining pattern to help identify neoplastic changes in situ.6,10,11,12 Histologic Findings Transmural involvement with noncaseating granulomas is seen in about 50% of cases of Crohn disease. Patchy skip lesions and lymphoid aggregates may also be seen throughout the bowel.4 Treatment Medical Care Diarrhea o Chronic diarrhea in Crohn disease responds well to antidiarrheal agents such as loperamide (2-4 mg), diphenoxylate with atropine (1 tab), and tincture of opium (8-15 gtt). Such agents may be administered up to 4 times daily, but they should not be given to patients with active colitis because of the risk of developing toxic megacolon. o Patients with terminal ileal disease may not absorb bile acids normally, which can lead to secretory diarrhea in the colon. These patients may benefit from bile acid sequestrants (eg, cholestyramine [2-4 g], colestipol [5 g] bid/tid ac). Those who have extensive ileal disease or resection of more than 100 cm of the ileum have defective bile salt absorption and develop steatorrhea. These patients benefit from a low-fat diet and mediumchain triglyceride preparations. Bile sequestrants exacerbate this type of diarrhea. o Diarrhea may also develop because of bacterial overgrowth, short-bowel syndrome, and lactase deficiency. o Abdominal cramps may be reduced with propantheline (0.125 mg), dicyclomine (10-20 mg), or hyoscyamine (0.125 mg). These drugs should not be used if there is the possibility of a bowel obstruction.2,13 For colon and small bowel inflammation, anti-inflammatory drugs or antibiotics are helpful. o Sulfasalazine is mainly useful in colonic disease, because the active compound, 5-aminosalicylic acid (5ASA), is released in the large bowel by bacterial degradation of the parent compound. Sulfasalazine does not alleviate small bowel disease. Products such as mesalamine (Asacol) that release 5-ASA in the distal small bowel secondary to pH changes are more useful in patients with small intestinal Crohn disease. Long-term maintenance with mesalamine (800 mg tid) may delay clinical relapse. Sulfasalazine does not have an additive effect or a steroid-sparing effect when used in conjunction with corticosteroids. In contrast to its action in ulcerative colitis, sulfasalazine does not seem to maintain remission in Crohn disease.

o A short course of steroid therapy is indicated in patients with severe systemic symptoms (eg, fever, nausea, weight loss) and in those whose condition does not respond to anti-inflammatory agents. Prednisone (40-60 mg/d) is generally helpful in acute inflammation. Once remission is achieved, the agent is slowly tapered (5-10 mg q1-2wk). It should be noted that steroids are not disease modifying and do not induce sustained mucosal healing. o In patients who relapse after the withdrawal of steroids, other treatment options are required. Steroids are not indicated for maintenance therapy because of serious complications, such as aseptic necrosis of the hip, osteoporosis, cataract, diabetes, and hypertension. o In patients with a tender, palpable mass, exclude the possibility of an underlying abscess before starting steroids. Adding antibiotics is always beneficial if coexisting infection is considered likely. o Consider immunosuppressants such as azathioprine (2 mg/kg/d) or its active metabolite, 6-mercaptopurine (6-MP), if steroid withdrawal proves difficult. Response is usually observed within 3-6 months. Careful supervision is needed because of the risk of bone marrow suppression. o If medical therapy fails, surgical resection of the inflamed bowel, with restoration of continuity, is indicated. Urgent surgery may be required in rare cases of sustained or recurrent hemorrhage and toxic megacolon. Partial small bowel obstruction may sometimes be treated conservatively with intravenous hydration, nasogastric suction, and parenteral nutrition if there is no evidence of adhesion or strangulation.2,13 Fistulae o Fistulae between bowel loops (eg, ileoileal, ileocecal, ileosigmoid) are usually benign and may not produce any major problems. o Enterovesicular, enterocutaneous, cologastric, and coloduodenal fistulae are more serious. Surgical intervention is rarely required, unless fistulae are complicated by progressive obstruction or abscess formation or a large segment of bowel is bypassed, leading to severe diarrhea and malabsorption. Otherwise, medical management is used to treat underlying infections and symptoms with oral metronidazole (1 g/d) for at least 12 months. Ciprofloxacin confers additional benefit if no improvement occurs. One study demonstrated that the combination of ciprofloxacin and metronidazole in 14 patients with perianal fistulae healed the fistulae in 3 patients and improved 85% of them. o Antimetabolites are beneficial in reducing drainage and closing fistulae in 30-40% of patients. Total parenteral nutrition (TPN) and bowel rest may promote fistulae healing during medical therapy. 2,13 New medical therapies o AntiTNF antibody TNF, a key inflammatory cytokine and mediator of intestinal inflammation, is expressed prominently in IBD. Infliximab is a chimeric mouse-human monoclonal antibody against TNF and shows promise in Crohn disease; it blocks TNF in the serum and at the cell surface, leading to the lysis of TNF-producing macrophages and T cells. In one study, nearly 65% of refractory cases of Crohn disease responded well to treatment with infliximab (5 mg/kg), and one third went into complete remission. Patients who relapsed after the initial response responded again to further infusions. Infliximab is also effective in patients who have refractory perianal and enterocutaneous fistulae. On average, the effect lasts for 12 weeks. Important adverse effects include the development of a lupus-like syndrome and an increased incidence of tuberculosis. Antidouble-stranded DNA is not always associated with clinical lupus. An added benefit of infliximab treatment is the ability to possibly taper steroids, which will decrease further adverse effects.14,15

 Unfortunately, infliximab is immunogenic, and repeated administration may result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy, and delayed hypersensitivity reactions.16 Two anti-TNF agents, adalimumab and certolizumab, may be less immunogenic than infliximab and have shown efficacy in the treatment of Crohn disease that is refractory to the standard medical treatment of corticosteroids and immunomodulatory agents.16 Adalimumab is a recombinant human immunoglobulin (Ig) G1 monoclonal antibody that binds with high affinity and specificity to human soluble TNF-alpha but not to lymphotoxin (TNF-beta). Results have shown that the immunogenicity of adalimumab is low compared with the chimeric mouse-human monoclonal antibody infliximab.16 Two placebo-controlled trials, CLASSIC I and CLASSIC II, showed that adalimumab was effective for both induction and maintenance of remission in patients who were previously naive to anti-TNF therapy. The CHARM trial demonstrated the same effect in a mixed population of patients who were either were naive to infliximab therapy or who had previously been on infliximab therapy. In patients who had lost response or become intolerant of infliximab, the GAIN trial results showed a benefit from adalimumab therapy induction with remission at 4 weeks. Furthermore, an open-label study conducted in France that assessed the long-term efficacy and safety of adalimumab maintenance therapy in this population showed that it was well tolerated and effective in maintaining clinical remission in patients who had Crohn disease with a lost response or intolerance to infliximab.9,17,18 Certolizumab pegol, a humanized Fab' antibody fragment conjugated to polyethylene glycol, has also demonstrated efficacy in maintaining remission in patients with moderately to severely active Crohn disease whose condition previously responded to induction therapy with the same agent (PRECISE trial). However, the data only covered a 6-month period.9 Immunosuppressive agents o Tacrolimus may be effective in treating Crohn disease. o Mycophenolate mofetil acts by inhibiting a de novo pathway of purine synthesis in lymphocytes, leading to intracellular depletion of guanosine monophosphate. This results in the suppression of cytotoxic T cells and the formation of antibodies by activated B cells. A dose of 500 mg twice a day in 2 divided doses is well tolerated by patients and can be used to reduce the steroid dose.2,13 o Anti-inflammatory cytokines: The use of IL-10 ilodecakin resulted in a trend toward clinical improvement but not remission in chronic active Crohn disease, and IL-11 oprelvekin was found to be effective in inducing remission in a preliminary study in patients with mild to moderate Crohn disease. However, more trials are needed.
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o Monoclonal antibody to IL-6 receptor tocilizumab has been suggested to have a beneficial clinical effect in Crohn disease as well as antibody to IL-12, which has been found to decrease the T helper-1 mediated inflammatory cytokines at the site of disease.2 o Natalizumab is a monoclonal antibody against the alpha4 integrin subunit that inhibits leukocyte adhesion and migration to areas of inflammation. Pooled clinical data suggest that this drug may be effective for inducing clinical response and remission, although trials were suspended due to 3 reported cases of progressive multileukoencephalopathy (PML) in 2 patients with multiple sclerosis receiving this agent in combination with IFN beta-1A.2

o Filgrastim or colony-stimulating factor (CSF) (granulocyte monocyte [GM]-CSF) has been shown to have a positive response to treatment in patients with fistulae. remission than placebo.2 Surgical Care Surgery plays an integral role in the treatment of Crohn disease to control symptoms and treat complications. By the 20 year of onset of symptoms, approximately 75% of patients with Crohn disease will have had surgery. Due to the high rate of disease recurrence after segmental bowel resection, the guiding principle of surgery is preservation of intestinal length and function.1 The recommended guidelines for those requiring surgery include persistent symptoms despite high-dose corticosteroids, treatment-related complications including intra-abdominal abscesses, medically intractable fistulae, fibrotic strictures with obstructive symptoms, toxic megacolon, hemorrhage, and cancer.
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o Fontolizumab is an antibody to IFN-gamma that has provided significantly better clinical response rates and

Fibrostenotic obstruction may require surgical correction; in some cases, endoscopic dilation is effective.

Patients with perianal fistulae will usually have a good response to medical treatment (eg, metronidazole, 6MP, cyclosporin [in refractory cases]). Surgical treatment is indicated if medical treatment fails or if an abscess is present.
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The postoperative recurrence rate remains high despite medical management in the postoperative period. The recurrence rate for patients undergoing total colectomy and ileostomy appears to be lower than for those undergoing segmental procedures.1 Diet The diet should be balanced in patients with Crohn disease. Fiber supplementation is said to be beneficial for patients with colonic disease due to the fact that dietary fiber can be converted to short-chain fatty acids, which provide fuel for colonic mucosal healing, whereas a low-roughage diet is usually indicated for patients with obstructive symptoms. Patients with Crohn disease of the small intestine often have lactose intolerance; therefore, avoidance of dairy products may be indicated. However supplementation with calcium may be required. Osteoporosis is a common nutritional complication of Crohn disease due to the above reason, as well as the release of cytokines from inflammatory cells, which stimulate osteoclast activity and lead to increased bone breakdown. Corticosteroid use is also another significant risk factor for the development of osteoporosis.
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Patients who undergo extensive resection of the terminal portion of the ileum may benefit from a low-fat diet with the addition of medium-chain triglyceride preparations. Enteral therapy with an elemental diet has been suggested to induce remission in acute Crohn disease, consumption of at least 1200 kcal/day was associated with lower rates of disease relapse, but patients' conditions have frequently relapsed after initiation of a normal diet. Indications for TPN o Short-term use: Patients with active inflammation and severe malnutrition and those with fistulae (given preoperatively) o Long-term use: Patients who have had extensive intestinal resection, resulting in short bowel syndrome13 Medication The goals of pharmacotherapy in patients with Crohn disease are to reduce morbidity, to prevent complications, and to maintain nutritional status.
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Anti-inflammatory agents Anti-inflammatory agents reduce inflammation by acting on host responses.

Mesalamine (Asacol, Rowasa, Canasa) Exerts anti-inflammatory effects. The mechanism of action is unknown, but it appears to act topically by modulating chemical mediators of inflammatory response. Available as PO or PR products. Adult PO: 800-mg DR tab tid for 6 wk; alternatively, 1-g DR cap qid for up to 8 wk PR: 500-mg PR supp bid for 3-6 wk or until remission (retain at least 1-3 h); alternatively, 4-g enema qhs for 36 wk or until remission (retain at least 8 h) Pediatric Not established Interactions: Decreases the effect of iron, digoxin, and folic acid; increases the effect of oral anticoagulants, methotrexate, and oral hypoglycemic agents Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Elderly persons may have difficulty in retaining rectal suppositories; caution in patients with renal or hepatic impairment Sulfasalazine (Azulfidine) Useful in the management of Crohn disease. Acts locally in the colon by decreasing the inflammatory response and systemically by inhibiting prostaglandin synthesis. Adult 3-5 g/d PO divided bid/tid Interactions: Decreases the effects of iron, digoxin, and folic acid; conversely, increases the effect of oral anticoagulants, oral hypoglycemic agents, and methotrexate Contraindications: Documented hypersensitivity; sulfa drugs or any component; diagnosed GI obstruction Precautions Caution in patients with renal or hepatic impairment, blood dyscrasias, or urinary obstruction B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Immunosuppressants Immunosuppressants interfere with the development of immunologic responses.

Infliximab (Remicade) Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-alpha and inhibits its binding to TNF-alpha receptors. Reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas. Dosing: Adult

5 mg/kg IV as single infusion over 2 h For fistulating Crohn disease, an induction and maintenance regimen may be required: 5 mg/kg IV infusion at 0, 2, and 6 wk as induction regimen, then 5 mg/kg q6wk for maintenance

IV infusion must be administered over at least 2 h; must use an infusion set with in-line, sterile, nonpyrogenic, low-protein-binding filter (pore size <1.2 micrometers) Pediatric Induction: 5 mg/kg IV infusion; repeat for total of 3 doses at 2 and 6 wk Maintenance: 5 mg/kg IV infusion q6wk Contraindications: Documented hypersensitivity to murine proteins or components of formulation; serious clinical infections. Precautions May adversely affect normal immune responses and allow development of superinfections; rare cases of lupuslike syndrome, demyelinating disorders, sepsis, tuberculosis, and fatal infections have been reported; discontinue treatment if sepsis or lupuslike syndrome develops C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus. Adalimumab (Humira) Recombinant human IgG1 monoclonal antibody specific for human TNF. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors. This interferes with cytokine driven inflammatory processes. It also lyses surface TNF-expressing cells in vitro in the presence of complement, but it does not bind to TNF-beta (lymphotoxin). Dosing: Adult Induction dose: 160 mg SC once (administer by either dividing dose into 4 injections on day 1 or over 2 days), then follow with 80 mg SC once at week 2 Maintenance: 40 mg SC q2wk beginning at week 4 Interactions: May interfere with the immune response to live virus vaccine (eg, MMR) and reduce efficacy; methotrexate (MTX) decreases clearance (available data do not support adjusting dose of either adalimumab or MTX); coadministration with anakinra (an IL-1 antagonist that also blocks TNF) may cause additive adverse effects, particularly the development of serious infections; use with echinacea may decrease its effect Contraindications: Documented hypersensitivity; active infection Precautions Causes immunosuppression; may be associated with serious infections (some fatal), including reactivation of tuberculosis, sepsis, or opportunistic infections; increases the risk for lymphoma development; associated with CNS demyelination (rare); may cause optic neuritis; discontinue if serious infection develops; autoantibody development may occur, causing lupuslike syndrome; may cause hypersensitivity reactions, including anaphylaxis and hematologic adverse effects (ie, pancytopenia, aplastic anemia); exacerbation of CHF or new onset CHF has been observed with TNF-blocking agents Certolizumab pegol (Cimzia) Pegylated antiTNF-alpha blocker, which results in disruption of the inflammatory process. Indicated for moderate to severe Crohn disease in individuals whose condition has not responded to conventional therapies. Dosing: Adult 400 mg SC initially; repeat at weeks 2 and 4; if favorable response occurs, initiate maintenance dose of 400 mg SC q4wk Administer as 2 separate 200-mg SC injections at 2 separate sites in abdomen or thigh

May interfere with the immune response to live virus vaccines (eg, MMR) and reduce efficacy; coadministration with anakinra (an IL-1 antagonist that also blocks TNF) may cause additive adverse effects, particularly the development of serious infections; may interfere with activated partial thromboplastin time (aPTT/aPPT) tests Precautions Common adverse effects include headache, upper respiratory tract infections, abdominal pain, injection site reactions, and nausea; increases the risk of serious infections, including infections that may result in hospitalization or death; may increase the risk of opportunistic infections (eg, tuberculosis [TB], invasive fungal), so test for latent TB, and, if positive, initiate TB treatment before starting certolizumab; if infection occurs, patients should contact their physician immediately; may cause reactivation of hepatitis B virus; may increase the risk of lymphoma and other malignancies because of immune suppression; anaphylaxis or serious allergic reactions, demyelinating disease, cytopenias, pancytopenia, heart failure, and lupuslike syndrome have been reported with TNF blockers Azathioprine (Imuran) Interferes with purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity. Dosing: Adult 1.5-2 mg/kg/d PO/IV Pediatric <3 years: Not established >3 years: 2 mg/kg/d PO/IV Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase the levels of methotrexate metabolites and decrease the effects of anticoagulants, neuromuscular blockers, and cyclosporine Contraindications: Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT) Precautions Increases the risk of neoplasia; caution in patients with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level before therapy, and monitor liver, renal, and hematologic function; pancreatitis is rarely associated Methotrexate (Rheumatrex, Trexall) Structural analogue to folic acid that inhibits binding of dihydrofolic acid to the enzyme dihydrofolate reductase. Dosing: Adult 25 mg IM with concomitant lowering of prednisone dose; once response is achieved, may switch to PO therapy; folic acid at dose of 1 mg/d should be given during treatment Oral aminoglycosides may decrease the absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase the hepatotoxicity of MTX; folic acid or its derivatives that are contained in some vitamins may decrease the response to MTX; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines Contraindications: Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency

Precautions Monitor CBCs monthly, and liver and renal function q1-3mo during therapy (monitor more frequently during the initial dosing, dose adjustments, or when the risk of elevated MTX levels is present [eg, dehydration]); MTX has toxic effects on the hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if a significant drop in blood counts occurs; fatal reactions have been reported when administered concurrently with NSAIDs Pregnancy X - Contraindicated; benefit does not outweigh risk Corticosteroids Corticosteroids exert both anti-inflammatory and immunosuppressant effects.

Prednisone (Deltasone, Orasone, Meticorten) Immunosuppressant for treatment of immune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Dosing: Adult 40-60 mg/d PO divided bid/qid; once in remission, slowly taper by 5-10 mg q1-2wk Coadministration with estrogens may decrease clearance; concurrent use with digoxin may increase the risk of digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing the maintenance dose); monitor for hypokalemia when coadministered with diuretics Contraindications: Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal skin infections or tuberculosis Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteoporosis, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, euphoria, psychosis, myasthenia gravis, growth suppression, and infections C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Budesonide (Entocort EC) Alters the level of inflammation in tissue by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in inflammatory reactions. Adult 9 mg (3 X 3-mg cap) qd for 8 wk Precautions Safety of treatment beyond 8 wk has not been established. Antibiotics Antibiotics are used in the treatment of bacterial infections that may be associated with the underlying disease processes.

Metronidazole (Flagyl)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Sometimes used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis). Also possesses immunosuppressive and anti-inflammatory properties. Adult 1 g/d PO divided bid/qid for 30-60 d May increase the toxicity of anticoagulants, lithium, and phenytoin; cimetidine may increase toxicity; disulfiram reaction may occur with orally ingested ethanol Precautions Adjust the dose in patients with hepatic disease; monitor for seizures and the development of peripheral neuropathy. Ciprofloxacin (Cipro) Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but it has no activity against anaerobes. Inhibits bacterial DNA synthesis, and, consequently, growth. Adult 500 mg PO bid Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT) Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in presence of renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy Follow-up Complications In the initial stages of Crohn disease, obstruction is caused by bowel edema and spasm, which is intermittent and reversible. Treatment involves conservative measures, such as nasogastric decompression, intravenous fluids, anti-inflammatory agents, and steroids (if required). If medical therapy fails, then surgical resection is necessary.
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Fistulae occur because of the penetration of a sinus tract through the bowel wall to the adjacent viscera. o Most fistulae are enteroenteric and enteromesenteric. They usually cause no symptoms and require no treatment. o Coloenteric fistulae and cologastric fistulae may result in bacterial overgrowth, diarrhea, and weight loss. o Enterovesical fistulae and enterovaginal fistulae are often complicated by infection. o Enterocutaneous fistulae usually occur at a previous surgical site, tracking the path of least resistance. o Many fistulae close with the use of TPN, but they recur when oral feeding resumes. A tender abdominal mass, fever, and leukocytosis indicate a possible underlying abscess. As many as 25% of patients with Crohn disease will present at some time in their lives with an abscess. Unfortunately, many patients at risk for perforation or abscess will be on glucocorticoids, which are known to suppress peritoneal

signs and fever and mask the presenting signs of infection. A CT scan helps confirm the diagnosis. Abscesses are treated with surgical drainage and broad-spectrum antibiotics. Severe hemorrhage is unusual in patients with Crohn disease.
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Malabsorption may occur for multiple reasons, such as bacterial overgrowth in an enterocolic fistula, strictures and stasis, extensive disease of the small bowel, and resection of large portions of the small intestine. Bile acid malabsorption may occur with extensive ileal disease, further exacerbating the malabsorption process.The steatorrhea that develops may lead to further complications, such as malnutrition, clotting abnormalities, calcium deficiency, and osteomalacia, which may progress to osteoporosis. Vitamin B12 deficiency may also occur with ileal resection or long-standing disease.1 Patients with colonic disease have an increased risk of colon cancer, which has been shown to be correlated with the extent and duration of the disease and the patient's age at onset. The role of colonoscopy as a screening tool in such cases is unclear. The risk of lymphoma secondary to medical therapy is still being investigated. Prognosis Although Crohn disease is a chronic condition with recurrent relapses, appropriate medical and surgical therapy helps patients to have a reasonable quality of life.
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Medical therapy becomes less effective with time, and surgery for underlying complications is required in nearly two thirds of patients at some point in their disease.1 The mortality rate increases with the duration of the disease, and GI tract cancer is the leading cause of disease-related death, including colorectal, small bowel adenocarcinoma, lymphomas, and squamous cell carcinomas arising in association with a chronic fistula to the skin. Some studies have also shown an association between Crohn disease and respiratory cancers.1 Acute regional enteritis, which is often discovered during laparotomy for suspected appendicitis, has an excellent prognosis. The acute episode is treated conservatively, and two thirds of patients may not have subsequent evidence of regional enteritis.1 Miscellaneous Medicolegal Pitfalls Avoid long-term steroid use in patients with Crohn disease. References 1. Kornbluth A, Sachar DB, Salomon P. Crohn's disease. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Sleisenger & Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, and Management. Vol 2. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998:1708-34. 2. Panes J, Gomollon F, Taxonera C, et al. Crohn's disease: a review of current treatment with a focus on biologics. Drugs. 2007;67(17):2511-37. [Medline]. 3. Tierney LM. Crohn's disease. In: Tierney LM, McPhee SJ, Papadakis MA, eds. Current Medical Diagnosis and Treatment. 40th ed. New York, NY: McGraw-Hill Professional Publishing; 2001:638-42. 4. Thoreson R, Cullen JJ. Pathophysiology of inflammatory bowel disease: an overview. Surg Clin North Am. Jun 2007;87(3):575-85. [Medline]. 5. Danese S, Semeraro S, Papa A, et al. Extraintestinal manifestations in inflammatory bowel disease. World J Gastroenterol. Dec 14 2005;11(46):7227-36. [Medline]. [Full Text].

6. Nikolaus S, Schreiber S. Diagnostics of inflammatory bowel disease. Gastroenterology. Nov 2007;133(5):1670-89. [Medline]. [Full Text]. 7. Fiocchi C. Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology. Jul 1998;115(1):182205. [Medline]. 8. Friedman S, Blumberg RS. Inflammatory bowel disease. In: Braunwald E, Fauci AS, Kasper DS, et al, eds. Harrison's Principles of Internal Medicine. Vol 2. 15 ed. New York, NY: McGraw-Hill Professional Publishing; 2001:1679-91. 9. Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut. Sep 2007;56(9):1232-9. [Medline]. [Full Text]. 10. Mackalski BA, Bernstein CN. New diagnostic imaging tools for inflammatory bowel disease. Gut. May 2006;55(5):733-41. [Medline]. 11. Saibeni S, Rondonotti E, Iozzelli A, et al. Imaging of the small bowel in Crohn's disease: a review of old and new techniques. World J Gastroenterol. Jun 28 2007;13(24):3279-87. [Medline]. [Full Text]. 12. Schreyer AG, Seitz J, Feuerbach S, Rogler G, Herfarth H. Modern imaging using computer tomography and magnetic resonance imaging for inflammatory bowel disease (IBD) AU1. Inflamm Bowel Dis. Jan 2004;10(1):45-54. [Medline]. 13. Robinson M. Optimizing therapy for inflammatory bowel disease. Am J Gastroenterol. Dec 1997;92(12 suppl):12S-17S. [Medline]. 14. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. May 6 1999;340(18):1398-405. [Medline]. [Full Text]. 15. Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. Oct 9 1997;337(15):1029-35. [Medline]. [Full Text]. 16. Peyrin-Biroulet L, Laclotte C, Bigard MA. Adalimumab maintenance therapy for Crohn's disease with intolerance or lost response to infliximab: an open-label study. Aliment Pharmacol Ther. Mar 15 2007;25(6):675-80. [Medline]. [Full Text]. 17. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial. Ann Intern Med. Jun 19 2007;146(12):829-38. [Medline]. [Full Text]. 18. Peppercorn MA. Clinical manifestations, diagnosis, and prognosis of ulcerative colitis in adults. UpToDate. Updated September 15, 2008. Available at http://www.uptodate.com/patients/content/topic.do?topicKey=~ufJTaZYEAmn5Gd. Accessed January 9, 2009. 19. Harpavat M, Keljo DJ, Regueiro MD. Metabolic bone disease in inflammatory bowel disease. J Clin Gastroenterol. Mar 2004;38(3):218-24. [Medline]. 20. Heuschkel R. Enteral nutrition in Crohn disease: more than just calories. J Pediatr Gastroenterol Nutr. Mar 2004;38(3):239-41. [Medline]. 21. Razack R, Seidner DL. Nutrition in inflammatory bowel disease. Curr Opin Gastroenterol. Jul 2007;23(4):400-5. [Medline].
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