Overview and Risk Factors
The most prevalent chronic inflammatory disorders of the digestive tract are ulcerative colitis and Crohn's disease, referred to collectively as inflammatory bowel disease (IBD). Approximately 1 million Americans have some form of IBD. Although the disorders share some clinical and pathologic features, each is a distinct condition. Crohn's disease can affect any part of the gastrointestinal tract from the mouth to the anus, often invading the deep layers of affected tissues, whereas ulcerative colitis affects the mucosa of the colon and rectum.
Causes of IBD have not been fully established, but the disorder is believed to be caused by abnormal immune system activation, which results in chronic inflammation and ulceration. Individuals with ulcerative colitis or pan-colitis have a higher risk of colon cancer, chronic active hepatitis, cirrhosis, arthritis, and nutritional deficiencies.
Genetics. Nod2 gene mutations are present in 30% of patients with Crohn's disease.
Environment. IBD is more common in developed countries, urban areas, colder climates, and among people of high socioeconomic status. Incidence also increases in populations that migrate from low-risk to high-risk areas.
Age. Onset usually occurs in people between the ages of 15 and 35.
Race. Whites have the highest risk. Also, Ashkenazi Jews have up to an 8-fold greater risk of developing IBD, compared with the general population. Caucasians and African Americans are more likely to have IBD than Hispanics and Asian Americans. Recently, however, Crohn's disease has become as frequent in Japan as in the United States, likely due to westernized lifestyle, including diet, increasing urbanization, and industrialization.
Family history. People with an affected relative have a 10-fold greater risk of having IBD. If the relative is first-degree, the risk is 20 to 35 times greater.
NSAIDs. Use of nonsteroidal anti-inflammatory drugs may trigger or cause relapse of IBD. Large intestinal ulcers, bleeding, strictures, and perforation are occasionally due to NSAIDs.1
Additional possible risk factors that require further study include the following:
Smoking. Studies on smoking and IBD risk, including maternal smoking during pregnancy and risk to the child for future IBD, show conflicting results.
Lack of breast-feeding. Some evidence suggests that breast-feeding may reduce risk, but more studies are needed to assess this possibility. See Nutritional Considerations for more information.
Crohn's disease and ulcerative colitis have many common symptoms, ranging from mild to severe, which may develop rapidly or gradually. These include:
Persistent diarrhea, which may be bloody and lead to dehydration.
Loss of appetite and subsequent weight loss. Children with IBD often fail to develop and grow properly.
Fever, which is a common sign in severe IBD cases.
Chronic inflammation, which may result in fissures, ulcers, fistulas, scarring, and strictures.
In severe cases, toxic megacolon may result, with an increased danger of colon perforation.
Extraintestinal manifestations include arthritis (more common in Crohn's disease); eye inflammations (conjunctivitis/uveitis); skin lesions (eg, erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis), which occur more often in Crohn's; anemia (primarily due to rectal bleeding); and liver disorders (mainly primary sclerosing cholangitis).
The following methods are often used to diagnose or evaluate IBD. Test selection depends on the type and severity of symptoms and previous test results. Invasive testing increases perforation risk and is not appropriate for patients with severe disease.
Endoscopic procedures, with or without biopsy, are recommended depending on the area of the digestive tract affected. Sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy (EGD), endoscopic retrograde cholangiopancreatography (ERCP), and capsule "minicamera" endoscopy can be used to diagnose and observe the extent of IBD. These tests can also rule out other diseases that may mimic IBD, such as cancer and hemorrhoids.
Radiologic tests provide important information that cannot be obtained through endoscopy alone. Plain abdominal x-ray can detect small bowel obstruction in Crohn's disease or toxic megacolon in ulcerative colitis. Barium swallow or enema can reveal strictures or intestinal fistula. However, neither one should be performed in cases of recent obstruction or severe inflammation.
CT scan may rule out complications of IBD (eg, intra-abdominal abscess, stricture, small bowel obstruction, fistula, and bowel perforation), narrow the differential, and aid in abscess drainage.
Complete blood count is used to check for anemia.
Tests for electrolytes, serum albumin, and carotenoid concentrations assess the possible consequences of malabsorption.
In 10% to 15% of patients, indeterminate colitis may be diagnosed through the perinuclear antineutrophil cytoplasmic antibody (P-ANCA) identified in ulcerative colitis, and the anti-Saccharomyces cervisiae antibody which typically indicates Crohn's disease.
Stool culture may be useful, because treatable bacterial infections can trigger an IBD flare.
The goal of treatment is to reduce the inflammation that triggers signs and symptoms and to induce remission. Treatment involves medication in mild to moderate cases, or surgery in severe and refractory cases. The following medications are commonly prescribed for patients with IBD:
Aminosalicylates. Sulfasalazine can be administered orally, in enema formulations, or as suppositories. However, it has numerous common side effects, which include infertility in men. Oral mesalamine has significantly fewer side effects for people who cannot tolerate sulfasalazine.
Corticosteroids. Prednisone, methylprednisolone, and hydrocortisone control inflammation in moderate-to-severe cases of IBD, but they all have numerous short-term and long-term side effects. Budesonide, however, is designed to be released specifically in the ileum and ascending colon, where Crohn's is most active. It is effective, and is rapidly metabolized and quickly cleared from the blood with relatively few side effects.
Broad-spectrum antibiotics. Ciprofloxacin, metronidazole, and ampicillin can be used as first-line therapy when purulent perianal disease is present, but are adjunctive therapies in flares of colonic Crohn's disease, in severe ulcerative colitis, in Crohn's disease unresponsive to other medical therapy, and in patients with severe side effects from other medications. These agents alter the bacterial composition of the intestines and suppress the intestine's immune system.2 Ciprofloxacin is preferred to metronidazole, which causes peripheral neuropathy when used chronically.
Immunomodulators. Azathioprine and mercaptopurine reduce the steroid dosage needed, aid in healing fistulas, and help maintain disease remission. Cyclosporine A is used in acute flares of ulcerative colitis resistant to other medications. These drugs have greater toxicity than corticosteroids and may cause kidney damage, hepatitis, hypertension, seizures, immunosuppression, and increased risk of lymphoma.
Biologic therapy (proteins, genes, and antibodies). These agents are used in patients who have not responded to conventional therapy. Infliximab is a chimeric monoclonal antibody that blocks the immune system's production of tumor necrosis factor-α. Adalizumab appears to have efficacy similar to that of infliximab.
The following treatments may be used for symptomatic relief:
Antidiarrheals, such as loperamide, may be effective.
Increased fiber intake should be encouraged when constipation occurs.
Iron supplements are used when chronic intestinal bleeding leads to iron-deficient anemia. When anemia is the result of chronic inflammation, erythropoietin may be required, in addition to iron supplements.
Vitamin B12 injections, high-dose oral administrations, or nasal sprays are needed in cases in which persistent diarrhea causes inadequate B12 absorption, or when the terminal ileum is affected in Crohn's disease. The vitamin also promotes normal growth and development in children.
Total colectomy may be necessary in severe cases of ulcerative colitis. Bowel resection is indicated in Crohn's disease when severe complications occur, including bleeding, strictures, and fistulas.
However, surgery is not usually curative. Postsurgery relapses can be reduced by continuous preventive treatment with 6-mercaptopurine or azathioprine, and possibly with aminosalicylates or metronidazole.
Psychological factors should be addressed. Studies suggest a role for psychologic stress in exacerbations of ulcerative colitis and a role for depression in Crohn's disease.3 A number of psychosocial factors (eg, gender, socioeconomic status, and ethnicity) appear to impact IBD.4 Limited evidence indicates that stress reduction reduces symptoms in patients with Crohn's disease, when compared with a control group treated conventionally,5 and results in less pain and decreased need for anti-inflammatory medication in patients with ulcerative colitis.6 However, clinical trials of such interventions are hampered by placebo effects and difficulties in securing a blind design.7 Additional studies are required.
Exercise. IBD patients can benefit from exercise. Although only limited evidence suggests that exercise reduces risk for the onset of IBD, benefits of regular activity include improvement of psychological symptoms; improvements in muscle strength and bone health, which are often impaired with glucocorticoid therapy; and a reduced risk for colon cancer that may result from long-standing IBD.8
Western diets high in animal protein and fat and low in fruit, vegetables, and fiber have been associated with the onset of IBD.9,10 Dietary changes may modify the risk for IBD or act as an adjunct to the anti-inflammatory treatments used to control disease activity.
Research studies have adduced several factors that may play a role in the risk of developing IBD:
Breast-feeding. Breast-feeding may protect against IBD by protecting against gastrointestinal infection during infancy; by stimulating the early development, maturation, and immunologic competence of the gastrointestinal mucosa; and by delaying exposure to cow's milk (see below).11 A meta-analysis found that the risk for ulcerative colitis was 25% lower and the risk for Crohn's disease 35% lower in individuals who were breast-fed.12
A Western dietary pattern. Western diets that are relatively high in meat, dairy products, and sugar, and low in fiber and other plant constituents, compared to diets that are traditional in other regions of the world, have been associated with a higher risk of IBD. It is difficult to identify specific aspects of the diet that are responsible for this pattern. Candidates that have been studied are discussed below. However, it may be that interventions to reduce risk need to address the overall dietary pattern, rather than its components.
Animal protein. Dietary data from Japan suggest that the westernization of traditional Asian diets is associated with increased risk for IBD. When the incidence of Crohn's disease and the daily intake of various dietary components were compared annually from 1966 to 1985, animal protein intake emerged as the strongest independent risk factor.13
Animal protein contributes significantly to the colonic sulfur pool, resulting in the generation of hydrogen sulfide. Hydrogen sulfide may increase disease activity in ulcerative colitis through a direct toxic effect on intestinal mucosa, and by interfering with butyrate oxidation, an important anti-inflammatory fatty acid produced from dietary fiber.14
Among patients with ulcerative colitis, meat intake per se more than triples the rate of relapse. Consumption of the highest, compared with lowest, intake of red meat and processed meat (172 g/day, compared with 124 g/day) increases the rate of relapse more than 5-fold.15 Conversely, a pilot study restricting animal protein and other dietary sources of sulfur resulted in a complete absence of IBD relapse, compared with an expected relapse rate of 22% to 26% with medication alone.16 Further studies are needed to confirm these effects.
On diets that provide vegetable sources of protein, fecal sulfide content is much lower than that of meat-based diets.17 This may help explain why epidemiological studies have found an inverse relationship between Crohn's disease prevalence and vegetable protein intake.13
Dairy products. Individuals with IBD reveal symptoms of sensitivity to cow's milk far more often than controls, and those who had documented cow's milk allergy developed ulcerative colitis at an earlier age than did people with this disease who were free of milk allergy. Patients with IBD have antibodies to cow's milk protein, and these correlate with disease activity in Crohn's disease.11 Studies also indicate that cow's milk increases both intestinal permeability and production of proinflammatory cytokines, both of which are involved in IBD.18 Preliminary data indicate that allergies to foods other than dairy products might be involved in IBD,19 but further study is required before hypoallergenic diets are established as an effective IBD treatment.
Some evidence suggests that a milk-borne pathogen may play an etiological role in Crohn's disease. Mycobacterium avium subsp. paratuberculosis (MAP) is commonly found in milk products, survives pasteurization, and causes a Crohn's-like illness (Johne's disease) in dairy cows and other ruminants. MAP has been found with far greater frequency in patients with Crohn's disease than in those with ulcerative colitis or controls.20 However, the pathogen has not yet been proven to be a causative agent in Crohn's, and the benefit of eradicating MAP with antibiotic therapy has not been established.20
High-fat diet. Fat intake may affect IBD through conversion of omega-6 fatty acids (found in animal products and vegetable oils (eg, corn, safflower and sunflower oil) to proinflammatory eicosanoids (eg, leukotriene B4).21 Diets that are high in fat, particularly animal fat, and cholesterol, have been associated with significant increases in the risk for IBD.9,10 The intake of foods containing partially hydrogenated fats is also associated with IBD risk. In countries where margarine consumption has increased, a rise in the rate of Crohn's disease followed.11 Persons eating fast foods (ie, foods high in hydrogenated oils) at least twice per week had 3 times the risk for Crohn's disease and 4 times the risk for ulcerative colitis, compared with those who avoided these foods.22
Low-fiber diet. Compared with persons consuming small amounts of fiber, those eating 15 grams or more per day had half the risk for developing Crohn's disease.22 Fruit intake in particular appears more strongly associated with reduced risk of IBD compared with cereals.11 Individuals eating high-fiber diets were more likely to remain in remission, or had significantly fewer and shorter hospitalizations and required less intestinal surgery, than a control group.23
Most high-fiber foods are also high in naturally occurring antioxidant vitamins, minerals, carotenoids, and flavonoids. These help to limit oxidative stress, a condition found in individuals with IBD as a result of intestinal inflammation,24 even in persons with low indices of disease activity while taking medication.25
High sugar intake. Studies have consistently found an association between higher intakes of sugars and the development of IBD.9,11 However, these associations may merely reflect lifestyle patterns common in populations with IBD. A biological mechanism has not been established for sugar's effect in IBD, and larger clinical trials have not documented significant benefits of a diet low in refined carbohydrates. Further studies are required to determine if such a diet helps to prevent or treat IBD.
In addition, the following dietary factors may play a role in clinical treatment:
Dietary supplements. Some patients with IBD may have significant malabsorption of nutrients. Others may have an increased need for certain antioxidants due to oxidative stress. Serum concentrations of several nutrients (beta-carotene, vitamin C, vitamin E, selenium, and zinc) were also significantly lower or outright deficient in IBD patients, as were antioxidant status and serum concentrations of magnesium and vitamin D.23,26 These deficiencies indicate a need for micronutrient-dense foods and a multiple vitamin-mineral supplement. Other types of dietary supplements, including fatty acids, botanicals, and probiotics, appear to be promising adjunctive approaches to IBD. Clinicians should consider prescribing the following nutrients for individuals with IBD:
B-vitamin supplements and plasma homocysteine. Many individuals with IBD have elevated levels of plasma homocysteine. In turn, recent evidence indicates that homocysteine plays a pathogenic, pro-inflammatory role in IBD.27 Lower levels of folate,28,29 vitamin B12,30,31 and vitamin B632 have been found in patients with IBD and elevated homocysteine. Clinical trials to assess benefits of lowering homocysteine levels with B vitamins in IBD have not yet been published. However, the folate-depleting effects of sulfasalazine may be involved with intestinal dysplasia, an abnormality preventable by folate supplementation.24
Vitamin K status is often poor in patients with Crohn's disease and is associated with higher levels of uncarboxylated osteocalcin and a greater rate of bone turnover.33,34 No evidence currently indicates that supplementation with vitamin K improves these indices. However, a high intake of vegetables containing vitamin K (eg, green leafy vegetables) is advised.
Omega-3 fatty acids. Some investigators have speculated that long-chain omega-3 fatty acids may decrease disease activity in IBD by reducing leukotriene B4 (LTB4) and other indices of immune overreactivity.23,24 Studies have suggested advantages of omega-3 supplementation in patients with ulcerative colitis,35 for reducing the rate of relapse in Crohn's disease,36 or as an adjunct to mesalazine for maintaining remission in pediatric patients with Crohn's disease.37 However, a review of omega-3 fatty acid supplementation studies found insufficient evidence to support conclusions about their effects on clinical, endoscopic, or histologic scores, or on remission or relapse rates.38
Probiotic therapy. Treatment with lactobacilli, streptococci, bifidobacteria, Saccharomyces boulardii, and certain E coli subspecies is based on several lines of evidence. These include: abnormal proliferation of harmful bacteria in the gut; the ability of "friendly" bacteria to augment lactic acid production, thereby reducing the luminal content pH and inhibiting growth of putrefactive or harmful bacteria; and a bacteriostatic effect against harmful bacteria. A number of clinical trials indicate reductions in disease activity and longer remission in patients with IBD who were treated with single or combined probiotics.24
What to Tell the Family
Research is suggestive, but has not yet established whether IBD is to some degree preventable through avoidance of a typical Western diet high in animal protein, animal fat, hydrogenated oils, and sugar, or through the addition of high-fiber foods. Evidence suggests that, in persons with established disease, these steps may improve the length of disease remission achievable with standard medical treatment, thus reducing the need for hospitalization and surgery.
1. Beaugerie L, Thiefin G. Gastrointestinal complications related to NSAIDs [in French]. Gastroenterol Clin Biol. 2004;28(Spec No 3):C62-C72.
2. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004;126:1620-1633.
3. Maunder RG. Evidence that stress contributes to inflammatory bowel disease: evaluation, synthesis, and future directions. Inflamm Bowel Dis. 2005;11:600-608.
13. Shoda R, Matsueda K, Yamato S, Umeda N. Epidemiologic analysis of Crohn's disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn disease in Japan. Am J Clin Nutr. 1996;63:741-745.
16. Roediger WE. Decreased sulphur amino acid intake in ulcerative colitis. Lancet. 1998;351:1555.
17. Magee EA, Richardson CJ, Hughes R, Cummings JH. Contribution of dietary protein to sulfide production in the large intestine: an in vitro and a controlled feeding study in humans. Am J Clin Nutr. 2000;72:1488-1494.
20. Sartor RB. Does Mycobacterium avium subspecies paratuberculosis cause Crohn's disease? Gut. 2005; 54:896-898.
21. Calder PC. Polyunsaturated fatty acids, inflammation, and immunity. Lipids. 2001;36:1007-1024.
26. Geerling BJ, Badart-Smook A, Stockbrugger RW, Brummer RJ. Comprehensive nutritional status in patients with long-standing Crohn disease currently in remission. Am J Clin Nutr. 1998;67:919-926.
29. Chowers Y, Sela BA, Holland R, Fidder H, Simoni FB, Bar-Meir S. Increased levels of homocysteine in patients with Crohn's disease are related to folate levels. Am J Gastroenterol. 2000;95:3498-3502.
30. Mahmood A, Needham J, Prosser J, et al. Prevalence of hyperhomocysteinemia, activated protein C resistance and prothrombin gene mutation in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 2005;17:739-744.
31. Romagnuolo J, Fedorak RN, Dias VC, Bamforth F, Teltscher M. Hyperhomocysteinemia and inflammatory bowel disease: prevalence and predictors in a cross-sectional study. Am J Gastroenterol. 2001;96:2143-2149.
32. Saibeni S, Cattaneo M, Vecchi M, et al. Low vitamin B(6) plasma levels, a risk factor for thrombosis, in inflammatory bowel disease: role of inflammation and correlation with acute phase reactants. Am J Gastroenterol. 2003;98:112-117.
34. Schoon EJ, Muller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrugger, RW. Low serum and bone vitamin K status in patients with longstanding Crohn's disease: another pathogenetic factor of osteoporosis in Crohn's disease? Gut. 2001;48:473-477.
35. Lorenz R, Weber PC, Szimnau P, Heldwein W, Strasser T, Loeschke K. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease--a randomized, placebo-controlled, double-blind cross-over trial. J Intern Med Suppl. 1989;731:225-232.
37. Romano C, Cucchiara S, Barabino A, Annese V, Sferlazzas C. Usefulness of omega-3 fatty acid supplementation in addition to mesalazine in maintaining remission in pediatric Crohn's disease: a double-blind, randomized, placebo-controlled study. World J Gastroenterol. 2005;11:7118-7121.
38. MacLean CH, Mojica WA, Newberry SJ, et al. Systematic review of the effects of n-3 fatty acids in inflammatory bowel disease. Am J Clin Nutr. 2005;82:611-619.