INFLAMMATORY BOWEL DISEASE

What is Inflammatory Bowel Disease?

The Gastrointestinal Tract.
The gastrointestinal (GI) tract (the digestive system) is a tube that extends from the mouth to the anus. It is a complex organ system that first carries food from the mouth down the esophagus to the stomach. There, acids and stomach motion break food down into particles small enough so that nutrients can be absorbed by the small intestine, which is, despite its name, the longest part—about 20 feet—of the GI tract. Food passes from the stomach into the small intestine, first entering the duodenum, then the jejunum, and finally the ileum. Next, residual material passes in liquid form into the large intestine, which consists of the colon and rectum and is about six feet long. The waste matter travels through the colon, forming into solid feces as the water is slowly absorbed. The first portion of the colon, which is located in the lower right quadrant of the abdomen, is called the cecum. From here, the large intestine travels to the upper right quadrant (where it is called the ascending colon), then across the abdomen to the upper left quadrant (the transverse colon), then down (the descending and sigmoid colon) to the rectum, which stores the feces until the sphincter muscles in the anus relax, allowing the solid waste matter to pass from the body.

Inflammatory Bowel Disease.
Inflammatory bowel disease (IBD) is a general term that includes both ulcerative colitis and Crohn’s disease, disorders of unknown causes that result in inflammation of the large or small intestines. Ulcerative Colitis. Ulcerative colitis is an inflammatory disease of the large intestine. Ulcers form in the inner lining, or mucosa, of the colon or rectum, often resulting in diarrhea, blood, and pus. The inflammation is usually most severe in the sigmoid and rectum and usually diminishes higher in the colon.

Crohn’s Disease. Crohn’s disease is an inflammation that extends into the deeper layers of the intestinal wall. It is found most often in the ileum and the first part of the large intestine (cecum), known as the ileocecal region. The disorder, however, can develop in any part of the gastrointestinal tract, including the anus, stomach, esophagus, and even the mouth. It may affect the entire colon, or form a string of contiguous ulcers in one part of the colon, or develop as multiple scattered clusters of ulcers.

What Causes Inflammatory Bowel Disease?
Although the cause of inflammatory bowel disease are not yet known, genetic factors play some role. Up to 25% of people with IBD also have family members with the disease. The inherited risk is highest if a mother has the condition, followed by a sibling.

A father with IBD poses the least inherited risk to his children. Although different genes play weaker or stronger roles in ulcerative colitis and Crohn’s disease, a recent study reported that genetic abnormalities of the two disorders may share locations on chromosomes 3, 7, and 12.

Some researchers believe that the disease develops because a genetic susceptibility enables an agent such as a virus or bacteria to trigger an abnormal immune response. If such organisms or other factors injure the lining of a healthy intestine, the immune system reduces inflammation and injury with white blood cells called suppressor T cells. In IBD, however, there appears to be an increase in white blood cells called helper-T cell, which produce damaging proteins known as cytokines. These proteins, particularly a powerful one called tumor necrosis factor, cause intestinal inflammation and damage, which, in a vicious loop, attract even more helper-T cells.

Different bacteria may be responsible for either Crohn’s or ulcerative colitis. Studies have found that children with IBD are likely to have more and earlier childhood infections than children without the disorder. Viral infections during pregnancy may also increase the child’s later risk for IBD. One study indicates that exposure to measles during pregnancy puts the baby at risk for developing Crohn’s disease, although not ulcerative colitis. Other suspects for Crohn’s disease is a tuberculosis-like organism.

Because inflammatory bowel disease is much more prevalent in industrialized nations, experts believe environmental factors, such as diet, must play some role. Diet studies have been conflicting. One study of dietary habits before patients developed IBD found that high fat intake—particularly animal fat—was associated with later development of ulcerative colitis. A high sugar intake (from non-fruit sources) was related to both inflammatory bowel disorders. A high intake of fluids and diets rich in fruits, vitamin C, and magnesium were associated with a lower risk of Crohn’s only.

What Are the Symptoms of Inflammatory Bowel Diseases?
Ulcerative colitis and Crohn’s disease share many symptoms, although they also differ in important ways. Both are chronic diseases and symptoms usually appear in young adults. In many patients, symptoms flare up (relapse) after symptom-free periods (remission); other patients have continuous symptoms, although medical treatments can bring about remissions even in many of these patients. Symptoms can be mild or very severe and disabling. They can develop gradually or have a sudden onset. The severity of symptoms and relapse rate also varies with seasons, with highest risk in the winter and autumn and lowest in summer.

Diarrhea.
The most common symptom of both ulcerative colitis and Crohn’s disease is diarrhea. Blood may also appear in the stools, especially with ulcerative colitis. The blood may be readily visible or visible only using a microscope, in which case it is called occult blood.

Constipation.
Constipation may develop during active flare-ups of both Crohn’s disease and ulcertive colitis. Constipation from Crohn’s disease usually occurs from an obstruction in the small intestine. In ulcerative colitis, constipation may occur when the inflamed rectum trigger a reflex response in the colon that causes it to retain the stool.

Abdominal Pain.
Cramps can occur from intestinal contractions caused by inflammation. The severity of the pain usually depends on the severity of diarrhea. Intestinal pain may also be an indication of a serious condition, such as- an abscess, or a perforation of the intestinal wall.

Other Symptoms.
Fever, fatigue and loss of appetite are often present, and the patient may lose weight. Tenesmus (a painful urge for a bowel movement even if the rectum is empty) can occur in response to inflammation. Neurologic or psychiatric symptoms may be early signs of Crohn’s disease when accompanied by gastrointestinal problems.

How Serious Is Inflammatory Bowel Disease?

Overall Outlook.
Outlook for Ulcerative Colitis. Surgical removal of the colon is the only cure for ulcerative colitis, but the disease varies greatly in severity. In one 10-year study, 87% of patients went into complete remission after a single attack and only 8% developed a chronic persistent condition. Overall mortality was the same as the general population, although it was higher in those with severe initial attacks or extensive disease.

Outlook for Crohn’s Disease. Crohn’s disease cannot be cured even with surgery. Although disease-free periods can be years to decades-long in some patients, recurrences tend to be the norm.

Determining Severity of Inflammatory Bowel Disease.
Ulcerative Colitis. Ulcerative colitis is considered mild if a patient has the following symptoms: four or less movements a day; only occasional blood in the stool; a normal temperature, pulse rate, and hemoglobin or red blood cell count; and no abnormalities observed on x-rays of the colon.

Ulcerative colitis is considered serious if the following symptoms are present: more than six movements a day; frequent to persistent blood in the stool; fever; a rapid pulse; anemia; abnormal x-rays of the colon; and tenderness in the abdomen when pressed, with possible distention.

Determining Severity of Crohn’s Disease. As with ulcerative colitis, the fewer movements, the milder the disease. In mild disease, abdominal pain is absent or minimal. The patient has a sense of well being that is normal or close to normal. There are few, if any, complications outside the intestinal tract. The physician does not detect any mass when pressing the abdomen. The red blood cell count is normal or close to normal, and the patient is not underweight.

In severe Crohn’s disease, the patient has frequent movements requiring opiates or other anti-diarrhea medication. Abdominal pain is severe. Pain in Crohn’s disease is usually in the lower right quadrant of the abdomen. (It should be noted, however, that the location of the pain may not be the site of the actual problem--a phenomenon known as referred pain.) The red blood cell count is low. The patient has a poor sense of well being and experiences complications that may include weight loss, joint pain, inflammation in the eyes, reddened or ulcerated skin, fistulas, abscesses, and fever.

Complications of Inflammatory Bowel Disease.
Toxic Megacolon. Toxic megacolon is a serious complication that can occur if inflammation in the colon spreads into its deeper layers. In such cases, the colon enlarges and becomes paralyzed. In severe cases, the colon may rupture, a surgical emergency that carries a 30% mortality rate. Symptoms include weakness and abdominal pain and bloating; the patient may be disoriented or groggy. X-rays are needed to confirm the diagnosis, but barium enemas and colonoscopies should not be performed. Toxic megacolon is more likely to occur with ulcerative colitis, but it can develop in Crohn’s disease. Unfortunately, medications used for pain and diarrhea, such as opiates, and drugs that reduce spasms of the colon, may increase the risk of toxic megacolon, although its incidence is decreasing as more effective treatments are developed.

Fistulas. The deep ulcers of Crohn’s disease frequently result in the development of fistulas, channels than can burrow between organs, loops of the intestine, or between the intestines and skin. If fistulas develop between the loops of the small and large intestines, they can interfere with absorption of nutrients. They often form pockets of infection or abscesses, which may become life threatening without treatment. Fistulas are rare in ulcerative colitis.

Intestinal Blockage. Inflammation from Crohn’s disease produces segments of scar tissue known as strictures that can constrict the passages of the intestines, causing bowel obstruction with severe cramps and vomiting. Strictures usually occur in the small intestine but can also occur in the large intestine.

Cancer. Chronic ulcerative colitis increases the risk for colon cancer. In different studies, this risk has been estimated to be 5% to 10% after 10 years and 15% to 40% after 30 years. People with ulcerative colitis should consider annual screening with colonoscopy beginning as early as age 25, depending on other risk factors, particularly any evidence of precancerous tissue (dysplasia). Individuals should discuss with their physician the risks and benefits of these screening procedures. Inflammatory bowel disease in the rectum and lower (sigmoid) colon does not significantly increase the risk for cancer. [For more information, see Well-Connected report #55, Colon and Rectal Cancers.]

Patients with Crohn’s disease of the colon have a similar risk for colon cancers. Other cancers, such as lymphoma or carcinoma of the small intestine or anus, may also be more common in patients with Crohn’s disease, but the risk is not high

Complications Occurring Outside the Gastrointestinal Tract. Many patients with inflammatory bowel disease experience inflammation in tissues beyond the gastrointestinal tract, the most common being joint inflammation. Others disorders include skin ulcers and swelling, mouth sores, inflammation of the eyes, hepatitis, and complications in the kidneys. Gallbladder disease and gallstones are common complications. Anemia can be caused by internal blood loss from ulcers in the intestine in both conditions and is a particular problem in Crohn’s disease, because of the impaired ability of the small intestine to absorb nutrients, including vitamins and minerals necessary for blood production. People with IBD are at higher risk for forming blood clots (thromboembolism). Women with inflammatory bowel disease have a higher risk for menstrual abnormalities, with 25% reporting problems in fertility. Half of women with Crohn’s disease report pain during sexual intercourse; almost 40% have ovarian cysts and 18% have had a hysterectomy—about half of them before age 35—mostly to relieve pain. People with Crohn’s disease tend to have an increased incidence of psoriasis, and one study has found a genetic link between the two disorders. Children with IBD, particularly Crohn’s disease, are at high risk for retarded physical growth.

Emotional and Neurologic Factors. Neurologic and psychiatric, complications occur with Crohn’s disease, and some experts believe that an autoimmune response affects the central nervous system. In any case, the emotional consequences of IBD cannot be overestimated. Eating becomes associated with fear of abdominal pain before the end of the meal. Frequent attacks of diarrhea can cause such a strong sense of humiliation that social isolation and low self-esteem may result. Strong support from family, friends, and health professionals are very important.

Who Gets Inflammatory Bowel Disease?
An estimated one to two million Americans suffer from inflammatory bowel disease. (This wide variation is mainly due to the difficulty in diagnosing these disorders and because people in remission may not be identified.) It was thought that Crohn’s disease was far less common than ulcerative colitis, but currently they are estimated to have about the same incidence. Males and females are equally susceptible. IBD is diagnosed most often between the ages of 15 and 40, but another lesser peak onset occurs between 50 and 80. About 2% of IBD cases appear in children below age 10; 30% occur in young people between the ages of 10 and 19. It often runs in families, and men and women are equally affected. Jewish people of European descent have a risk of IBD five times that of the general population. The condition appears more frequently in the U.S., Western Europe, Canada, New Zealand, and Australia than in other parts of the world, indicating that both genetic factors and environmental conditions, such as diet, may be involved in its development. IBD appears to be more common among city than country dwellers.

How is Inflammatory Bowel Disease Diagnosed?
The physician will take a history and give a thorough physical examination. Blood tests that show an increased number of white blood cells may indicate the presence of inflammation. A stool sample is taken and examined for blood or infections. The disease is particularly difficult to diagnose in children, in whom it may be mistaken for an infection or even depression if other characteristic symptoms, such as bloody diarrhea and weight loss, are not present. Slow growth may be a key feature in making a diagnosis, particularly of Crohn’s disease. Blood tests are usually abnormal in children with IBD.

Procedures Used for Diagnosis.
Endoscopic Procedures. Flexible sigmoidoscopy and colonoscopy are procedures that involve snaking a fiberoptic tube called an endoscope through the rectum to view the lining of the colon. The physician can also insert instruments through it to remove tissue sample. Sigmoidoscopy, which is used to examine the rectum and left (sigmoid) colon, lasts about 10 minutes and is done without sedation. It may be mildly uncomfortable, but it is not painful. Colonoscopy allows a view of the entire colon and requires a sedative, but it is still performed on an outpatient basis.

The procedures may help the physician to distinguish between ulcerative colitis and Crohn’s disease, as well as other diseases. Ulcerative colitis almost always involves the lower left colon and rectum and is diagnosed using sigmoidoscopy. The physician usually observes an evenly distributed inflamed surface lining the intestine, and the bowel wall bleeds easily when touched with a swab. The pattern observed in Crohn’s disease is usually one of scattered patches of ulcers that are deeper, thicker, and larger than those found in ulcerative colitis. Under a microscope, tissue samples obtained from a patient with Crohn’s disease may reveal granulomas, small collections of inflammatory cells; granulomas may also be present in other conditions. Tissue samples may also be examined for the presence of cancer.

Upper and Lower Gastrointestinal Barium X-Ray. An upper gastrointestinal barium x-ray may be used if Crohn’s disease is suspected in the small intestine. Swallowed barium passes into the small intestine and shows up on x-ray image, which may reveal inflammation, ulcers, and other abnormalities. A barium enema x-ray is usually required to view the colon. This procedure should not be done during active periods of disease, because it increases the risk for toxic megacolon.

Computed Tomography ((CT) Scans. Computed tomography (CT) scans are proving to be useful in evaluating active IBD.

Diseases Resembling Inflammatory Bowel Disease.
Irritable Bowel Syndrome. Irritable bowel syndrome (IBS), also known as spastic colon, functional bowel disease, and spastic colitis causes many of the same symptoms as inflammatory bowel disease. Bloating, diarrhea, constipation, and abdominal cramps are all symptoms of IBS. There is no fever or bleeding with this disorder, however, and it is not caused by inflammation. Behavioral therapy may be helpful in treating irritable bowel syndrome (no psychologic therapy improves inflammatory bowel disease).

Infections. If endoscopy reveals inflammation, infections must be ruled out before making a diagnosis of inflammatory bowel disease.

Cancer. Colon or rectal cancers must always be ruled out when symptoms of IBD occur.

What Are the Drug Treatments and Dietary Measuresfor Inflammatory Bowel Disease?
Drugs cannot cure inflammatory bowel disease, but they are effective in reducing the inflammation and accompanying symptoms in up to 80% of patients. Many such drugs are available, including corticosteroids, aspirin-like medications, and drugs that suppress the immune system. The primary goal of drug therapy is to reduce inflammation in the intestine. The success of therapy is determined by its ability to induce and maintain remissions without incurring significant side effects. The patient’s condition is generally considered in remission when the intestinal lining has healed and symptoms, such as diarrhea, abdominal cramps and tenesmus, are normal or close to normal. It is more difficult to define remission in Crohn’s disease than in ulcerative colitis, because diagnostic test results do not always correlate with a patient’s symptoms or complications outside the intestine.

Mesalamine (5-Aminosalicylic Acid) and Its Preparations.  Mesalamine is the common name of the compound 5-aminosalicylic acid or 5-ASA, which inhibits substances in the immune system, particularly leukotrienes, that cause inflammation. Mesalamine itself is very effective and has few side effects, but it is quickly absorbed in the upper gastrointestinal tract before it can reach the colon. In developing drugs using mesalamine, other substances or formulations have been needed to allow 5-ASA to reach the intestine before it is absorbed. Some of the substances have proven to have severe side effects.

Sulfasalazine. Sulfasalazine (Azulfidine) has been the standard mesalamine, or 5-ASA, preparation for years. In ulcerative colitis, sulfasalazine is useful for treating mild to moderate attacks and for maintaining remission. It is helpful for some Crohn’s disease patients whose active condition occurs in the colon, but it is not effective in the small intestine and does not prevent recurrence. One study has found, however, that long-term therapy is protective against colon and rectal cancers in patients with ulcerative colitis.

Sulfasalazine combines mesalamine with sulfapyridine, a sulfa antibiotic that prevents mesalamine from being absorbed until it reaches the colon. There, intestinal bacteria break sulfasalazine into its two components. The active component, mesalamine, blocks the inflammatory process; the other component, sulfapyridine, however, plays no positive role in the colon, and, in fact, its sulfa properties are responsible for most of the adverse side effects and allergic responses experienced by up to 30% of patients taking this drug. Some common side effects include heartburn, headache, loss of appetite, abdominal discomfort, dizziness, anemia, fever, and rashes. The drug may temporarily lower sperm count in men and can turn urine a bright orange-yellow color. Rare but serious side effects include a lupus-like disorder, pancreatitis, liver damage, and blood disorders. Some of these blood disorders can become life-threatening (although very rarely), so blood counts should be performed regularly, particularly during the first few weeks of treatment. Sulfasalazine can also cause folic acid deficiency, and patients should take supplements of this important B vitamin. Withdrawal of sulfasalazine (and, in fact, most major drugs used for IBD) when the disease is still active can trigger a severe relapse.

Mesalamine Formulations. Drugs using mesalamine alone have now been developed with different formulations that allow it to reach the lower intestine without incurring the adverse side effects of the sulfa component used in sulfasalazine. Like sulfasalazine, such drugs are effective for mild to moderate ulcerative colitis and Crohn’s disease. They are also effective for maintaining remission in ulcerative colitis. For patients with Crohn’s disease, mesalamine is slightly effective for maintaining remission, although mostly in certain groups of patients, including those whose disease is in the colon or combined colon and small intestine—not for those whose problem is only in the small intestine. It also seems to benefit women more than for men.

Under the brand name Rowasa, mesalamine can be administered rectally using enemas or suppositories. Mesalamine enemas have been reported to help 80% to 90% of patients with ulcerative colitis of the lower colon. Rectal administration in such patients both relieves mild to moderately active disease and prevents relapse. Mesalamine is not usually administered rectally for Crohn’s disease, although some people with disease of the left colon may benefit. The enemas are administered at night with the patient lying on the left side and instilled for about 8 hours. The treatment continues every night for 4 to 8 weeks or until the lining has healed.

Oral mesalamine is used for treating active attacks of mild to moderate IBD and for preventing relapse of ulcerative colitis. It appears to be less successful in maintaining remission of Crohn’s disease. Different drug brands have been designed using coatings or time-released formulations to prevent mesalamine from being absorbed in the upper intestine. Some brands include: Asacol (effective in the last section of the ileum and the colon); Pentasa (in the stomach and colon); Claversal, Mesasal, and Salafalk (in the ileum and colon), and Balsalazide (in the colon). A combination of oral and rectal forms may be used in certain cases. One study has found that taking patients with severe ulcerative colitis who took 5-ASA orally daily and as an enema twice a week had significantly fewer relapses than people taking only an oral form.

Mesalamine has a chemical structure similar to aspirin. People allergic to aspirin, therefore, should not take any of the 5-ASA drugs or preparations, including sulfasalazine. About 5% or less of those taking oral mesalamine experience diarrhea. All 5-ASA preparations, including sulfasalazine, appear to be safe for children and for women who are pregnant or nursing. Mesalamine does not adversely affect sperm count fertility, as sulfasalazine does. Oral mesalamine, particularly Asacol, may slightly increase the risk for kidney damage, although this is a very rare event. Other less severe side effects of all oral forms of mesalamine are skin disorders, nausea, cramps, itchiness, anxiety attacks, and inflammation of other organs, although one study reported that mesalamine caused no more side effects than placebos (inactive substances, such as sugar pills, used in drug studies). Unfortunately these drugs are more expensive than sulfasalazine.

Olsalazine. Olsalazine (Dipentum) is similar to sulfasalazine, in that the drug stays intact until it reaches the intestine and is then broken down by intestinal bacteria into two components, one of which is mesalamine. Unlike sulfasalazine, however, the other component is a harmless molecule similar to mesalamine, which does not have sulfapyridine’s adverse side effects. Olsalazine does, however, cause diarrhea in 15% of those taking the drug, which may be minimized by starting out with lower doses and taking the medication with meals. Olsalazine is approved in the US only for people with ulcerative colitis who cannot take sulfasalazine and only to prevent relapses. It is not approved for treating attacks, but many physicians prescribe it for this purpose, although taking it during active periods may further increase the risk for diarrhea.

Adrenal Corticosteroids.
Adrenal corticosteroids (commonly called steroids) are powerful anti-inflammatory drugs, usually used only for active ulcerative colitis and Crohn’s disease. They do not prevent relapses and have serious long-term effects, so they are not useful for maintenance therapy. Corticosteroids are sometimes combined with other drugs to produce more rapid symptom relief and to allow sooner withdrawals from the steroids. Combinations, however, do not increase remission time. Prednisone, prednisolone, hydrocortisone, and methylprednisolone are the most commonly used steroids. Newer steroids, such as budesonide, beclomethasone, and tixocortol, are being developed to affect only local areas in the intestine and not to circulate throughout the body, which can cause widespread side effects—a serious problem with standard steroids. Some of these newer drugs may even eventually prove to be safe for maintenance therapy. Corticotropin (ACTH), which stimulates natural production of steroids, is favored by some physicians, but it is effective only in certain patients and is not in common use.

Steroids can be taken orally, intravenously, by injection, or rectally as a suppository, enema, or foam. In general, enemas, suppositories, and, in limited cases, foam preparations are used for patients with mild to moderate ulcerative colitis located in the left section of the colon, the rectum, and anus. For moderate to severe ulcerative colitis and Crohn’s disease, oral preparations, usually of prednisone or prednisolone, are used. (An oral form of the new drug budesonide may be as effective as and safer than prednisolone for Crohn’s disease in the ileum and cecum regions.) If the patient requires hospitalization, intravenous steroid therapy, with or without rectal steroids, are administered initially. (If these drugs are not effective after a week of intravenous therapy, they are not likely to work.) Once bowel movements are normal and the patient can eat, oral doses replace intravenous and rectal forms, and then they are tapered gradually. Patients less likely to respond to steroids include those who are malnourished and those who are receiving a repeat treatment after an initial inadequate response.

Side Effects. Steroids can have distressing and sometimes serious long-term side effects, including susceptibility to infection, weight gain (particularly increased fatty tissue on the face and upper trunk and back), acne, excess hair growth, hypertension, accelerated osteoporosis, cataracts, glaucoma, diabetes, wasting of the muscles, and menstrual irregularities. Personality changes can occur, including irritability, insomnia, psychosis, and depression, sometimes severe enough to produce suicidal thoughts. Growth may be retarded in children. Drug-induced diabetes, swelling, and hypertension can be minimized with other treatments. Infections which develop during corticosteroid therapy should be treated promptly. Vaccines are available to help prevent influenza and pneumonia. Supplemental calcium and vitamin D are important to help to preserve bone mass against osteoporosis.

Once the intestinal inflammation has subsided, steroids must be withdrawn very gradually in order to give the body time to recover its own ability to produce natural steroids. Withdrawal symptoms, including fever, malaise, and joint pain may also occur if the dosage is lowered too rapidly. In such cases, particularly since the symptoms of withdrawal may resemble those of inflammatory bowel disease, the dosage is increased slightly and maintained until symptoms are gone. More gradual withdrawal is then resumed.

Immunosuppressive Drugs.
For very active inflammatory bowel disease that does not respond to standard treatments, immunosuppressant drugs are now being used for long-term treatment. All of these drugs suppress actions of the immune system and therefore its inflammatory response that causes ulcerative colitis and Crohn’s disease. The two most common immuno-

suppressants used for IBD are azathioprine (Imuran) and mercaptopurine (Purinethol). When one of these drugs is combined with a corticosteroid during active attacks, lower doses of the steroids are needed, resulting in less side effects. Corticosteroids may also be withdrawn more quickly when accompanied by an immunosuppressant. These drugs, then, are sometimes referred to as steroid-sparing drugs. They cannot replace steroids for an initial attack, because it takes azathioprine or mercaptopurine three to six months to become effective, although they work more rapidly for subsequent attacks. Immunosuppressants can, however, prevent relapse when used alone, and in some studies have proved to be effective for maintaining remissions in ulcerative colitis that have lasted at least two years. They also appear to help maintain remission in Crohn’s disease, and appear to heal fistulas and intestinal ulcers caused by this disease. A study of Crohn’s disease patients reported that mercaptopurine was safe for long-term use.

Other immunosuppressants being investigated for IBD and showing promise in promoting short-term remission include cyclosporine (Sandimmune) and methotrexate (Folex). Cyclosporine may be useful for Crohn’s disease accompanied by fistulas, but it does not seem to be beneficial for long-term maintenance. It is also showing promise for ulcerative colitis and some studies are reporting a more rapid onset of action (two weeks) compared to the other immunosuppressants. Serious complications, some life-threatening, can occur, however, in patients with ulcerative colitis who do not respond favorably to both cyclosporine and corticosteroids. Experts recommend that cyclosporine be used only by ulcerative colitis patients who have previously responded favorably to steroids and who can be closely monitored by knowledgeable specialists.

Side Effects. Although experts have been concerned about dangerous side effects based on experience with immunosuppressants used in transplant operations, the lower doses of the drugs required for IBD and other inflammatory disorders may make them safer in the long run than steroids, and they are being increasingly used for maintaining remission. The most frequent side effects of immunosuppressants are not serious and include stomach and intestinal distress, rash, numbness or tingling in the hands and feet, mouth sores, and hair loss (or excessive hair growth with cyclosporine). It should be noted, however, that the actions of immunosuppressant damage certain rapidly-growing immune system cells, including those that produce antibodies, causing an increased risk for infection. Oversuppression of the immune system can result in low blood cell counts as well and other serious side effects. These include anemia, herpes zoster (shingles), hepatitis, bladder toxicity, and menstrual irregularity with possible sterility. (Sterility in female patients may be averted by administering pulsed doses at the time of menstruation.) Some increase in blood cancers has been associated with the use of azathioprine for other disorders, but there is no clear evidence that this risk is increased in patients taking the drug for IBD. Between 3% and 15% of patients taking immuno- suppressants develop pancreatitis; in such cases immunosuppressants should never be used again. Symptoms of pancreatitis usually occur within the first few weeks and include nausea, vomiting, and upper abdominal pain that may radiate to the back.

Metronidazole and Other Antibiotics.
Metronidazole (Flagyl) is an antibiotic used for infections caused by anaerobic bacteria, which are organisms that can exist without oxygen and often cause abscesses and abdominal and gynecologic infections. Metronidazole is useful for people with Crohn’s disease whose condition is accompanied by bacterial overgrowth, abdominal abscesses, and infections around the anus and genital areas. Metronidazole also has anti-inflammatory effects and may prove to be as useful in general for Crohn’s disease as sulfasalazine. In one study it helped prevent recurrence after surgery, although side effects were severe. Other antibiotics used for Crohn’s disease include trimethoprim/sulfamethoxazole (Bactrin, Cotrim, Septra), ciprofloxacin (Cipro), and tetracycline. Withdrawal brings on relapse, so long-term therapy is required, carrying a risk for side effects, including numbness and tingling in the hands and feet. Antibiotic therapy does not seem to provide much benefit for ulcerative colitis, other than for complications after surgery.

Experimental Drugs.

Anti-Tumor Necrosis Factor Antibodies and Other Immune-Modifying Drugs. Researchers continued to explore drugs that modify the immune system. Of some promise is a genetically engineered antibody (CDP571) that acts against tumor necrosis factor (TNF), a major factor in the inflammatory process that causes IBD. Recent trials are showing promise in reducing disease activity and improving symptoms in both Crohn’s disease and ulcerative colitis. A similar drug, cA2, is also showing promise against Crohn’s disease.

4-Aminosalicylic Acid. A variant of mesalamine, 4-aminosalicylic acid, is being studied for IBD.

Fatty Acids and Fish Oil. Patients with ulcerative colitis appear to have low concentrations in their feces of fatty acids, including one known as butyrate; this substance has been tested in enema preparations with some success. One study found that large doses of fish oil, which is rich in fatty acids, improved Crohn’s disease. Patients, however, disliked the fishy breath and side effects, including flatulence, heartburn, belching, and diarrhea. Recently, a coated preparation of fish oil was tested and was found to prevent relapse for at least a year in 60% of patients.

Nicotine. Some patients with ulcerative colitis have reported that their disorder began after they quit smoking, and many studies have reinforced the association between smoking and protection against ulcerative colitis. Studies are showing that the nicotine patch helps to induce remission and reduce symptoms in almost 40% of patients who use it for four weeks. Another study found, however, that patches are not useful for maintaining remission of symptoms. Side effects, particularly in nonsmokers, include nausea, lightheadedness, and headache. (No one should smoke for relief of ulcerative colitis symptoms; the risks in cigarettes far outweigh the potential benefits of their nicotine.)

It should be noted that smoking has the opposite effect for Crohn’s disease; there are more smoking patients with Crohn’s disease than non-smokers. In one study, when smokers with the disease quit, the incidence of relapse was reduced by 40% over a year.

Treatments for Symptoms and Complications.
Diarrhea and Constipation. In patients with mild to moderate disease, diarrhea may be reduced by taking one teaspoon of psyllium hydrophilic colloid (Metamucil) twice a day in a glass of water. Mild diarrhea is sometimes treated with opiates, although they should never be used for severe diarrhea. Drugs specifically used for muscle spasms can help relieve diarrhea and abdominal cramps, but such drugs should be used for very short periods and not for severe cases. In large amounts, certain antidiarrheal drugs may even trigger onset of toxic megacolon in very ill patients, bulk-type laxatives can help constipation.

Treatment of Anemia. Iron supplements may be needed for anemia. The hormone erythropoietin, which acts in the bone marrow to increase the production of red blood cells, is being tested severe anemia caused by IBD that does not respond to iron pills alone. In studies, symptoms of anemia are reduced, but erythropoietin is very expensive.

Antidepressants. Antidepressants may help patients who have emotional difficulties, but it should be stressed that inflammatory bowel disease is not caused by psychologic disorders, and such drugs will not affect the basic illness.

Pain-Relievers. Acetaminophen, sold as Tylenol and other common brands, is the drug of choice for mild pain. Acetaminophen is not one of the nonsteroidal anti-inflammatory drug, (NSAIDSs), which includes, among dozens of others, aspirin, ibuprofen (Advil, Motrin, Rufen), naproxen (Anaprox, Naprosyn, Aleve). NSAIDs often used against other inflammatory disorders, but they have been implicated in triggering inflammatory bowel disease; one study found that they doubled the risk for emergency treatment of gastrointestinal symptoms in patients with colitis. NSAIDs, therefore, should be avoided for IBD.

Diet.
Food Recommendations. Children with inflammatory bowel disease may suffer from malnutrition, probably a major factor in growth retardation. Some experts recommend that children be given an increase in calorie and protein intake of 150% of the daily recommended allowance for their specific age and height. Studies indicate that nutritional support in children is as important as medications for achieving remission.

Although no evidence exists that any specific foods reduce inflammation, one study has indicated that certain foods are associated with a lower or higher risks for developing IBD. The foods linked to a lower risk were fruits (for both IBD disorders) and vegetables (for Crohn’s disease). Foods most often blamed for aggravating existing symptoms are milk and milk products, spicy foods, fats, and sugars. When symptoms erupt, physicians recommend a bland, low-fiber diet. Surgery may increase the risk for absorption of oxalate, a substance that reacts with calcium to form kidney stones. Surgical patients should avoid foods high in oxalate, including spinach, rhubarb, beets, coffee, tea, diet sodas, and chocolate. Patients should drink plenty of fluids.

Vitamin and Mineral Supplements. Crohn’s disease itself and surgical procedures that remove parts of the small intestine can inhibit absorption of vitamins, fats, calcium, and magnesium. Iron supplements and monthly injections of vitamin B-12 may be necessary in such cases. Folic acid supplements may be important for patients who must restrict fresh fruits and vegetables and for those taking sulfasalazine. In general, vitamin supplements may be recommended for all patients with IBD, particularly for children to avoid growth retardation; taking large doses of vitamins, however, may be harmful.

Elemental Diets. Elemental diets are liquids that are fully nutritional and are sometimes helpful in improving symptoms, reducing relapses, and improving nutrition in Crohn’s disease patients. Included in the nutritional solution is a large amount of glutamine, an amino acid that provides energy for the lining of the small intestine. The solution has an unpleasant metallic taste and some health professionals recommend adding flavored toppings or instant coffee and drinking the liquid cold to improve its taste. Commercial and less expensive liquid diets, such as Ensure, Sustacal, and others that meet full nutritional needs and are absorbed in the upper intestine may also beneficial for Crohn’s disease, but this is still unproven.

Parenteral Nutrition. If Crohn’s disease becomes very severe and patients cannot tolerate any nutrition by mouth, they may need total parenteral nutrition (TPN), or hyperalimentation, which is the intravenous administration of nutrients through an indwelling catheter (tube). Infection is a risk with this procedure. Patients with ulcerative colitis may be required TPN if they are malnourished, require surgery, or have very severe disease.

Surgery for Ulcerative Colitis.
In 20% of patients, drug therapy is not effective and surgery is necessary. Surgery may also be required because of hemorrhage, chronic illness, perforation of the colon, or to prevent colon cancer. For a complete cure, a procedure called proctocolectomy is performed in which the entire colon and rectum are removed. Since the lower part of the rectum is removed, including the sphincter muscles that control bowel movements, an ileostomy is required. With this procedure, the surgeon makes a small opening in the lower right corner of the abdomen through which the cut ends of the small intestine are brought out. A bag is kept over the opening, which accumulates waste matter and requires emptying several times a day.

Other procedures have been developed so that some patients may not need to use an ileostomy bag. Ileoanal anastomosis takes advantage of the fact that ulcerative colitis does not extend to deeper layers of the colon. The colon is removed but only the superficial diseased inner layer of the rectum is stripped, leaving the sphincter muscles intact. The anus is then attached to the ileum (the final portion of the small intestine leading to the colon), and a pouch is constructed out of the small bowel above the anus to collect waste material. A temporary ileostomy is usually required, which is closed in a second operation three months later. The patient then can pass bowel movements normally through the anus, although they may be watery and more frequent. In about 5% to 10% of cases, complications occur that are severe enough to require conversion to an ileostomy. Some experts stress that the procedure be performed only on patients in whom it is clear that ulcerative colitis is causing the IBD, in order to reduce the possibility of finding underlying Crohn’s disease or other problems that increase the risk for complications.

Another operation, continent ileostomy, may be used for patients whose rectal muscles are not strong enough for ileoanal anastomosis or who have already had an ileostomy and want a more convenient arrangement. The surgeon forms a pouch for collecting waste from the last few inches of the ileum. A valve is created in the abdominal wall through which a tube is inserted to drain waste material from the pouch. At first the pouch is drained eight to ten times a day, but eventually it needs to be emptied only about half as many times. This procedure may need to be done in two stages, with an ileostomy bag worn for several months before the pouch can be made. Recent advances, however, have allowed surgeons to complete the procedure in one operation unless the patient is very ill. In continent ileostomies, the valve may leak or the catheter may become blocked; in at least 10% of these procedures, the valve needs to be repaired later on. The continent ileostomy is becoming obsolete, in favor of the ileoanal pouch procedure.

The most common complication of both procedures is inflammation of the pouch (pouchitis), which can usually be treated easily. (In one study about 4.5% of patients developed chronic pouchitis, which caused increased defecation and required long-term medication.) Severe scarring at the incision occurs in more than half of patients; a recent study found that placing an experimental absorbable membrane made from hyaluronate (a natural lubricating substance) along the incision reduced the rate of scarring to 15%.

Surgery for Crohn’s Disease.
Crohn’s disease cannot be cured with surgery, because new disease can appear in other areas of the intestine. Surgery, however, may be helpful for relieving symptoms and to correct blockage, perforation, fistulas, or bleeding. Infrequently, the entire colon is removed and an ileostomy created. In most cases, only the part of the colon that is diseased is removed, a procedure called resection. The antibiotic, metronidazole, may be helpful in preventing recurrence of Crohn’s disease after surgery. If large segments of the small intestine are removed, short-bowel syndrome may develop, in which there is a problem absorbing nutrients. To prevent this problem in some patients, a procedure called strictureplasty has been developed that involves cutting and stitching only the areas obstructing the intestine, so that it widens the intestine without removing sections of it.

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Modified April 22, 1999 - Four M Engineering, Inc