Inflammatory Bowel Disease
The major idiopathic chronic inflammatory disorders of the digestive tract are ulcerative colitis and Crohn’s disease, collectively referred to as inflammatory bowel disease (IBD). Approximately 250 per 100,000 people in North America have some form of IBD., Although these disorders share some clinical and pathologic features, they are distinct conditions.
Crohn’s disease can affect any part of the gastrointestinal tract from the mouth to the anus. It is a transmural disorder, meaning it can invade the deep layers of affected tissues. Endoscopic examination typically reveals “skip lesions” reflecting the noncontiguous nature of the disease. The ileum and the proximal colon are the most commonly affected areas.
Ulcerative colitis is limited to the colon and affects only the mucosal layer. A diagnosis of indeterminate colitis is made when physicians cannot definitively identify either ulcerative colitis or Crohn’s disease through colonoscopy, colonic biopsy or at colectomy. Most patients diagnosed with indeterminate colitis will eventually be diagnosed with either ulcerative colitis or Crohn’s disease. Indeterminate colitis patients often have overlapping features of both ulcerative colitis and Crohn’s disease to variable degrees.
Causes of IBD have not been fully established, but the disorders are believed to be caused by a combination of genetics and environmental factors., Individuals with ulcerative colitis or pancolitis have a higher risk of colon cancer, autoimmune hepatitis, cirrhosis, arthritis, and nutritional deficiencies.
In some patients, the same pathologic process of immune-mediated inflammation in the gut may affect many other organ systems as well. These include uveitis, multiple sclerosis, primary sclerosing cholangitis, ankylosing spondylitis, pyoderma gangrenosum, and erythema nodosum, among others. Some extraintestinal manifestations may parallel mucosal disease activity such as oral aphthous ulcers, anterior uveitis, inflammatory arthralgia, and erythema nodosum.
Genetics. There are over 200 well-described gene mutations associated with the development of Crohn’s disease., In particular, NOD2 gene mutations are present in a significant percentage of patients with Crohn’s disease. NOD2 gene mutations are present in up to 20% of the general population as well, and do not alone predict the development of Crohn’s disease. However, in patients with Crohn’s disease, the presence of NOD2 gene mutations may be of utility in predicting development of ileal disease and possibly need for surgical resection.
Environment. IBD is more common in developed countries, urban areas, and colder climates, as well as among people of high socioeconomic status. Incidence also increases in populations that migrate from low-risk to high-risk areas.
Diet. Diets high in total fats, polyunsaturated fatty acids, omega-6 fatty acids, and meat are associated with an increased risk of Crohn’s disease and ulcerative colitis.
Race. In the US, non-Hispanic whites are more likely to have IBD, compared with Hispanics, Blacks, and Asian Americans, though there is a disproportionately higher ratio of hospitalizations and surgeries among Blacks than in other groups. The prevalence of Crohn’s disease is increasing in Japan and other Eastern countries, likely due to Westernized lifestyle, including diet.
Family history. People with an affected relative have a greater risk of having IBD.
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.
Additional possible risk factors that require further study include the following:
Smoking. Studies on smoking and IBD risk, including those evaluating maternal smoking during pregnancy and risk to the child for future IBD, show conflicting results. Overall, smoking appears to be associated with increased risk for Crohn’s disease and reduced risk for ulcerative colitis.,
Lack of breastfeeding. Some evidence suggests that breastfeeding may reduce risk, but more studies are needed to assess this possibility. See Nutritional Considerations for more information.
Early antibiotic use. Limited evidence links antibiotics used in early life to IBD.
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.
Abdominal pain is much more common in Crohn’s disease than in ulcerative colitis.
Loss of appetite and subsequent weight loss. Children with IBD, particularly Crohn’s disease, often fail to develop and grow normally.
Fever can be a sign of a flare of severe IBD.
Chronic inflammation, which may result in fissures, ulcers, fistulas, scarring, and strictures within the colon.
In severe cases of ulcerative colitis, toxic megacolon may result, which carries an increased danger of colon perforation.
Extraintestinal manifestations are common in inflammatory bowel disorders. Arthritis is particularly common in Crohn’s disease. Inflammatory conditions of the eye include conjunctivitis and uveitis. Skin lesions include erythema nodosum, pyoderma gangrenosum, and aphthous stomatitis; these occur more often in Crohn’s disease. Rectal bleeding can lead to anemia.
Liver disorders can also occur, particularly sclerosing cholangitis. Roughly 70-80% of patients with primary sclerosing cholangitis also have IBD.
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. Note that invasive testing during a flare increases perforation risk and is not appropriate for patients with severe disease.
Endoscopic procedures are recommended to assist with diagnosis. Sigmoidoscopy, colonoscopy, esophagogastroduodenoscopy (EGD), enteroscopy, endoscopic retrograde cholangiopancreatography (ERCP), and capsule endoscopy can be used to diagnose and categorize 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 (e.g., intra-abdominal abscess, stricture, small-bowel obstruction, fistula, and bowel perforation), narrow the differential, and aid in abscess drainage.
Unlike CT scans, MRIs do not use ionizing radiation and are therefore preferred.
Complete blood count is used to check for anemia, particularly iron deficiency anemia. Overt blood loss seen in ulcerative colitis and occult blood loss as seen in Crohn’s disease can both lead to iron deficiency. Also, the inflammatory states of all illnesses under the IBD umbrella can prevent the active absorption of dietary iron from the intestine.
Inflammatory markers such as stool calprotectin, c-reactive protein (CRP), and sedimentation rate (ESR) can help suggest the diagnosis and can be used to monitor inflammation noninvasively.
Tests for electrolytes, iron, ferritin, vitamin D, and vitamin B12 assess the possible consequences of malabsorption. Serum albumin may be used as a nonspecific marker for malabsorption and overall gauge of toll on a patient’s nutritional status.
A diagnosis of colitis may be suggested by testing for the presence of perinuclear antineutrophil cytoplasmic antibody (P-ANCA) in ulcerative colitis and anti-Saccharomyces cerevisiae antibody (ASCA) in Crohn’s disease. However, these alone are not used for diagnosis as inflammatory bowel disease requires endoscopic and histologic confirmation.
During workup and during flares, mimicking diseases should be ruled out with stool studies, including stool culture, Clostridium difficile PCR, ova and parasites, giardia, and cryptosporidium. Infections, particularly Clostridium difficile, can trigger an IBD flare.
The goal of treatment is to reduce inflammation and induce endoscopic remission. Symptom-free remission does not always correlate with endoscopic remission. Treatment involves medication in mild to moderate cases and surgery in severe and refractory cases. Emergent surgery may be required for perforations or uncontrolled bleeding. If surgery is indicated, laparoscopic surgery performed by a colorectal surgeon is preferred.,
The following medications are commonly prescribed for patients with IBD:
Aminosalicylates. Sulfasalazine is used in ulcerative colitis and can be administered orally, in enema formulations, or as suppositories. However, it has numerous common side effects, which include infertility in men and should not be used in pregnant women. Oral mesalamine is more frequently prescribed and can be administered orally or rectally through suppositories or enemas for more distal disease. Meta-analyses demonstrate that aminosalicylates have not been shown to be effective in inducing remission in patients with Crohn’s disease.
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 and should not be used for maintenance. Budesonide, however, is designed to be released specifically in the ileum and ascending colon, where Crohn’s disease typically is most active. It is effective and is rapidly metabolized and quickly cleared from the blood with relatively few side effects, though it should not be used in Crohn’s disease maintenance beyond 4 months duration. A differently coated version, budesonide multi-matrix, is taken orally and coats the entire large intestine providing utility in treating mild to moderate ulcerative colitis flares.
Broad-spectrum antibiotics. Ciprofloxacin, metronidazole, and ampicillin can be used as first-line therapy when purulent perianal disease is present, but they are only 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. 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 are used in refractory disease, having greater toxicity than corticosteroids, including the possibility of causing kidney damage, hepatitis, hypertension, seizures, and immunosuppression and increasing the risk of lymphoma. Methotrexate, although not FDA approved for the treatment of IBD, has been used in conjunction with biologics by many clinicians. Both azathioprine and methotrexate are used along with some biologics to decrease immunogenicity to biologic medication and increase biologic drug levels.
Biologic therapy (proteins, genes, and antibodies). These agents are used in patients who have not responded to conventional therapy and provide immunosuppression without the use of steroids and their debilitating side effects.
Anti-Tumor Necrosis Factor (anti-TNF’s) agents: Infliximab is a chimeric monoclonal antibody that blocks the immune system’s production of tumor necrosis factor-α. Adalimumab appears to have efficacy similar to that of infliximab. Other anti-TNF agents, which differ in route of administration, dosing frequency and possible immungenocity include certolizumab and golimumab. Anti-TNF agents should be used to treat steroid-resistant moderate-to-severe Crohn’s disease, as well as Crohn’s disease that is refractory to thiopurines or methotrexate. They are also very effective in fistulizing Crohn’s disease.
Anti-Integrins: Natalizumab, an antibody that prevents leukocyte trafficking to tissues, was first developed to treat multiple sclerosis but was also found to be effective in treating Crohn’s disease. However, natalizumab carries a small but increased risk of progressive multifocal leukoencephalopathy. Therefore, it is utilized in very specific circumstances. Subsequently, development of an anti-integrin that prevented lymphocyte trafficking via gut-trophic α4β7 heterodimers was developed: vedolizumab. Vedolizumab is indicated in both Crohn’s disease and ulcerative colitis.
Anti-IL-12/23: Ustekinumab is an anti-p40 antibody that inhibits IL-12 and -23, and should be given to patients with moderate-to-severe Crohn’s disease and ulcerative colitis who have failed previous treatment with corticosteroids, thiopurines, methotrexate, or anti-TNF inhibitors, or who have had no prior exposure to anti-TNF inhibitors.
Anti-TNF’s, ustekinumab and vedolizumab, have been shown to have a favorable safety profile in clinical trials, making them each a good first choice of biologic in both Crohn’s disease and ulcerative colitis,
Small molecules, JAK inhibitors: Tofacitinib is the first small molecule to be approved for the treatment of moderate-to-severe ulcerative colitis. It is not approved for Crohn’s disease. It is an oral pill and has an onset of action within days in patients who respond to the medication in contrast to the current biologics which are delivered by intravenous or subcutaneous route and may take several weeks to elicit a response.
Currently, there are no prognostic assays to predict to which treatment a patient will respond. However, clinical characteristics of the individual patient’s disease, personal preference, severity of disease and prior treatment history may help dictate which agent is first recommended by a physician.
The following treatments may be used for symptomatic relief:
Antidiarrheals, such as loperamide or diphenoxylate-atropine, may be effective.
Increased fiber intake should be encouraged for all patients with IBD. It is recommended that patients consult their gastroenterologist and registered dietician when changing their diet and to work closely with them if a stricture is present to prevent obstructive symptoms. Notably, patients with strictures may be sensitive to the physical passage of fiber, particularly during a flare.
Iron supplements are used when chronic intestinal bleeding leads to iron-deficient anemia (see Nutritional Considerations). Intravenous iron infusions may be needed in patients with small bowel disease when oral absorption is not optimal. Chronic inflammation can also contribute to anemia and may necessitate additional testing and treatment.
Vitamin B12 injections, high-dose oral or nasal administration, are needed in cases in which persistent diarrhea impairs B12 absorption or when the terminal ileum is affected in Crohn’s disease. In either case, evidence for decreased body stores of vitamin B12 is usually indicated before starting lifelong replacement therapy. Studies have shown that high-dose oral administration is as effective as intramuscular supplementation when given to correct any etiology of deficiency.
Exercise. IBD patients 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.
Microbial flora. The bacterial flora of affected individuals differs from that of healthy individuals. Decreased diversity of gut flora has been associated with more severe IBD symptoms. Dysbiosis is often present in patients with IBD, characterized by a diminished number of healthy species with a greater presence of pro-inflammatory species, a reduction in short-chain fatty acid production, and an impaired gut barrier function. It has not been established if these differences are the cause of effect of IBD.,
Surgery. Surgery is not curative in either ulcerative colitis or Crohn’s disease. In severe or medically refractory cases of ulcerative colitis, a total proctocolectomy may be necessary to re-establish good quality of life in patients. Bowel resection is indicated in Crohn’s disease when severe complications occur, including bleeding, strictures, abscesses and fistulae. In Crohn’s disease, it is not uncommon for the disease to recur post-operatively. In the post-operative patient with Crohn’s disease, a follow-up colonoscopy should be pursued in 6-12 months to assess for disease recurrence. In patients with prior ileal disease, a Rutgeerts score of the neo-ileum should be determined post-operatively, as this has been demonstrated with good prognostic ability to predict need for recurrent surgical intervention without effective treatment. If a patient is deemed to be high risk for recurrence, biologics are usually initiated at this time.
The Crohn’s and Colitis Foundation has produced a list of recommended vaccines and health screenings for IBD patients. In general, most IBD patients on immunosuppressive therapy should avoid live vaccines. Each immunosuppressive agent is unique, and patients should individually consult with their personal physician as to the safety and appropriateness of each individual vaccine that they should receive.
All patients should receive an annual influenza vaccine (non-live), Tdap (or a booster every 10 years), HPV (all patients older than 26 years), hepatitis A and hepatitis B (check titers), and zoster (recombinant vaccine). Varicella and MMR should be given only if the patient is not immune and should have IgA titers checked. Group B meningococcal meningitis vaccine should only be given to patients aged 16 – 25 who are high risk. Patients on anti-TNF therapy or those older than age 65 should receive PCV13 and PPSV23.
All patients on systemic immunosuppression should have a yearly full-skin screening and a colonoscopy every 1-3 years, and women should have an annual cervical PAP smear. All patients at high risk of bone loss, particularly all women age 65 and older, should have a DEXA scan.
Western diets high in animal protein and fat and low in fruit, vegetables, and fiber rich foods have been associated with the onset of IBD.,, Dietary changes may modify the risk for developing 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:
Absence of breastfeeding. Breastfeeding may reduce the risk of developing IBD, presumably by protecting against gastrointestinal infection during infancy; by stimulating the early development, maturation, and immunologic competence of the gastrointestinal mucosa and gut microbiome; and by delaying exposure to cow’s milk (see below)., 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 breastfed. No longitudinal, interventional studies have been conducted to demonstrate the efficacy of breastfeeding to prevent IBD in the offspring of parents with IBD.
A Western dietary pattern. Western diets emphasizing meat, dairy products, and sugar, while deficient fiber and other plant constituents, have been associated with a higher risk of IBD. While it is difficult to identify which aspects of the diet are responsible for this association, a systematic review of 19 studies looking at IBD patients found that high intakes of total fats, polyunsaturated fats, omega-6 essential fats, and meat were associated with an increased risk for IBD while fiber, fruit, and vegetables were associated with a decreased risk.,, Ultimately, however, interventions to reduce risk need to address the overall dietary pattern, rather than its components.
Animal protein. A review of prospective studies found that adults who consumed the most animal protein, particularly from meat (including fish), were at increased risk for IBD. 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.
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. Animal products in general lower gut microbiota diversity, triggering IBD.
Among patients with ulcerative colitis, meat intake per se more than triples the rate of relapse. Consumption of the highest, compared with the lowest, intake of red meat and processed meat (172 g/d, compared with 124 g/d) increases the rate of relapse more than 5-fold. 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 22-26% with medication alone. 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. This may help explain why epidemiologic studies have found an inverse relationship between Crohn’s disease prevalence and vegetable protein intake.
A prospective single group, inpatient trial included 26 adults and 11 children with new onset Crohn’s disease, and 9 adults who were unresponsive to medical therapy, were put on standard induction therapy with infliximab infusions and a vegetarian diet. The remission rate was 96%, compared to a 30% remission with infliximab alone. It was proposed that the plant-based diet reduces inflammation while restoring and maintaining gut symbiosis.
Dairy products. Individuals with IBD often have symptoms of sensitivity to cow’s milk. IBD patients with 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 may have antibodies to cow’s milk protein, and these correlate with disease activity in Crohn’s disease. Some studies demonstrate that cow’s milk increases both intestinal permeability and production of proinflammatory cytokines, both of which are involved in IBD. Preliminary data indicate that allergies to foods other than dairy products might be involved in IBD, 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 etiologic role in Crohn’s disease. Mycobacterium avium subsp. paratuberculosis (MAP) is commonly found in milk products, survives pasteurization, and causes a Crohn’s disease-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. However, the pathogen has not yet been proven to be a causative agent in Crohn’s disease, and the benefit of eradicating MAP with antibiotic therapy has not been established.
High-fat diet. Fat intake may affect IBD through conversion of omega-6 fatty acids (found in animal products and vegetable oils, such as corn, safflower, and sunflower oil) to proinflammatory eicosanoids (e.g., leukotriene B4). Diets that are high in fat, particularly animal fat, and cholesterol have been associated with significant increases in the risk for IBD.,, 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.
Individuals eating fast foods at least twice per week had approximately 3 times the risk for Crohn’s disease and approximately 4 times the risk for ulcerative colitis compared with those who avoided these foods.
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. Fruit intake in particular appears more strongly associated with reduced risk of IBD compared with cereals., 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.
In addition to their fiber content, vegetables and fruits also provide antioxidant vitamins, minerals, carotenoids, and flavonoids. These compounds help limit oxidative stress, a condition found in individuals with IBD as a result of intestinal inflammation, even in persons with low indices of disease activity while taking medication., This is not a reason for supplementation, however. These compounds are easily obtained from dietary sources; their role in IBD management has yet to be established.
High sugar intake. Studies have consistently found an association between higher intakes of sugars and the development of IBD.,, 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) have been found to be significantly lower or outright deficient in IBD patients, as are antioxidant status and serum concentrations of magnesium and vitamin D., These deficiencies indicate a need for micronutrient-dense foods and a multivitamin-mineral supplement.
However, oral forms of iron may be contraindicated. Although iron-deficiency anemia is common in patients with IBD due to gastrointestinal blood loss, oral iron supplements have been found to exacerbate disease by causing oxidative stress on gut mucosa, while intravenous iron does not.,
Clinicians should consider prescribing the following nutrients for individuals with IBD:
B-vitamin supplements. Many individuals with IBD have elevated levels of plasma homocysteine. In turn, recent evidence indicates that homocysteine plays a pathogenic, proinflammatory role in IBD. Lower levels of folate, vitamin B12, and vitamin B6 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 in intestinal dysplasia, an abnormality preventable by folate supplementation.
Vitamin D levels are inversely associated with intestinal inflammation and positively associated with quality of life among those with IBD.
Although the optimal supplementation dose has yet to be determined, 1,800-10,000 IU/day, depending on the patient, and aiming for serum levels between 30 and 50 ng/mL, appears to be safe and effective.
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., No evidence currently indicates that supplementation with vitamin K improves these indices. However, a high intake of vegetables containing vitamin K (e.g., 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., Studies have suggested advantages of omega-3 supplementation in patients with ulcerative colitis, for reducing the rate of relapse in Crohn’s disease or as an adjunct to mesalazine for maintaining remission in pediatric patients with Crohn’s disease.,, However, a review of studies on supplementation of omega-3 fatty acids found insufficient evidence to support conclusions about their effects on clinical, endoscopic, or histologic scores, or on remission or relapse rates.
See Basic Diet Orders chapter.
What to Tell the Family
Evidence suggests that Western diets emphasizing animal-derived food products, hydrogenated oils, and processed foods may increase the risk of IBD. While the role of dietary changes in modifying the course of IBD is under investigation, individuals with inflammatory bowel diseases may wish to make dietary changes as described above, under the guidance of a gastroenterologist and registered dietician. Their families can assist them in making these changes and may benefit themselves from these same diet adjustments.
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