Sunday, January 8, 2012

Ulcerative colitis

Authors : Alan C. Moss MD Beth Israel Deaconess Medical Center, Adam S. Cheifetz MD Center for Inflammatory Bowel Disease, Mark A. Peppercorn Harvard Medical School Boston MA

2008-07-29

Introduction
:

Ulcerative colitis is a disease characterised by chronic inflammation of the colon (colitis) accompanied in severe cases by ulcers in the lining of the colon (ulcerations). It is most often diagnosed in people between the ages of 15 and 30, although it can develop at any age, in both children and adults. The majority of patients have inflammation in their rectum, which spreads along the colon to varying extents.The inflammation may be limited to the rectum (proctitis) or rectum and sigmoid colon (distal colitis) or rectum, sigmoid and descending colon (left-sided colitis). When at least two-thirds of the colon is affected it is termed “extensive colitis.” “Pancolitis”is the term used when the entire colon is inflamed. Ulcerative colitis is a chronic condition in which individuals experience both periods of active disease (flares/relapses) and periods of mild or inactive disease (remission). Typical symptoms include diarrhea, which is often bloody, and abdominal pain. Typical treatment involves anti-inflammatories or medications that suppress the immune system. Occasionally, medical treatment fails and surgical removal of the diseased colon becomes necessary. This knol reviews the causes, symptoms and treatment of ulcerative colitis.

What causes it?

Ulcerative colitis is predominantly a disease of the the developed world, and is uncommon in the developing world, possibly due to a higher prevalence of intestinal infections in the developing world. The exact reasons why some individuals develop ulcerative colitis are unknown, although a number of inherited and enviromental factors increase the risk of developing the disease.Essentially, the condition is caused by an inappropriate response by an individual’s immune system to bacteria normally present in the colon. To trigger the colonic inflammation that is the hallmark of the condition, the presence of a particular mix of colonic bacteria in a susceptible individual is probably required. The evidence for the role of bacteria comes from the observation that animals that are susceptible to developing colitis due to genetic mutations do not develop inflammation if kept in a bacteria-free enviroment. Although the colon normally contains over 1 billion bacteria, no single organism has been identified as the cause of ulcerative colitis. Similarly, the association between genetic mutations and ulcerative colitis is relatively weak, and thus no single genetic test for ulcerative colitis currently exists [1]. A variety of inherited deficiencies in the control of immune responses to bacteria in the colon may allow normally benign bacteria to invade the colon. Interestingly, ulcerative colitis is less common in smokers, and patients who stop smoking are at increased risk of a flare of the disease. Some speculate that nicotine or its metabolites may have protective properties in strengthening colonic defences. As the precise triggers for the disease are unclear, current treatment focuses on suppressing the immune response that has been activated.

What are the symptoms?

The typical complaints of someone with ulcerative colitis are frequent diarrhea, which is often bloody (Table 1) [2]. Patients with severe disease often report defecating 15-20 times a day. Moderate to severe colitis also can cause diarrhea at night, a strong urge to pass stool that is difficult to ignore (urgency) and, occasionally, incontinence of stool (feces). Prolonged diarrhea may lead to weight loss in severe cases. Yet paradoxically, patients who have disease localised to the rectum can also be constipated. The extent of the disease, as well as its severity, influences which symptoms are dominant.

Table 1 : symptoms in ulcerative colitis
- diarrhea
- crampy abdominal pain
- bloody stool
- urgency
- incontinence of stool
- weight loss
- fevers
- joint pains


In addition, crampy lower abdominal pain is common, which is often relieved by passing stool. The pain is usually on the lower left side, but may be across the entire abdomen. A feeling of distension and bloating may also be present. About 30-50% of patients experience symptoms outside the intestinal tract, including joint pains, skin rashes, and eye irritation. Fever may occur during severe flares of the disease. Anemia can occur due to blood loss. As with many chronic diseases, malnutrition, psychological stress, and work disability may become problematic as a consequence of persistent active disease. Fertility may be affected by active disease, as well as by medications or surgery for the disease. Unfortunately the symptoms described above are not exclusive to ulcerative colitis. In young adults with new-onset diarrhea, infections of the colon are the most important causes to consider. Where this has been excluded, then ulcerative colitis is an important consideration.

Other conditions that produce similar symptoms to ulcerative colitis include:

Irritable Bowel Syndrome, which can cause diarrhea and crampy abdominal pain, but bleeding and night-time diarrhea are unusual.
Intestinal infections (Clostridium difficile, Salmonella, Shigella and Campylobacter), which can cause profuse diarrhea, rectal bleeding, fevers and abdominal pain (infectious colitis).
Crohn’s disease of the colon, which may cause similar symptoms to ulcerative colitis, but usually the colon is inflamed only in a patchy manner.
Insufficient blood supply to the colon, which in older patients can cause bloody diarrhea and severe abdominal pain (ischemic colitis).
Celiac disease, microscopic colitis, bacterial overgrowth and lactose intolerance are among the other conditions that can cause diarrhea and crampy abdominal pain without bleeding.

All of the symptoms above require medical attention, but symptoms alone are insufficient to diagnose ulcerative colitis. Nevertheless, once the diagnosis is established, changes in symptoms are a reliable way of determining whether the disease is active or not.

How is it diagnosed?

The most accurate way to diagnose ulcerative colitis is by examining the colon with a fibre-optic endoscope inserted into the rectum (sigmoidoscopy if only the lower third of the colon is examined, colonoscopy if the full colon is examined). This requires a bowel cleansing preparation to ensure the lining of the colon can be seen. When ulcerative colitis is present, the lining of the colon appears swollen and inflammed, with surface bleeding and ulcers usually in a continuous pattern (Figure 1). Tiny samples (biopsies) of the lining of the colon are taken during the procedure, so that a pathologist may examine them under the microscope for inflammatory changes (histology). This combination of endoscopy and histology is the gold standard for diagnosis of ulcerative colitis. Nevertheless, in patients with signs of severe colitis, this procedure may be postponed as the lining of the colon becomes very fragile and easy to damage with the endoscope.

Abdominal CT scans can detect thickening of the colonic lining, and identify the extent of involvement of the colon, but cannot distinguish between ulcerative colitis and other types of colitis (see above). Examination of the stool under the microscope is important to exclude infections of the colon that can cause similar symptoms to ulcerative colitis. Even patients known to have ulcerative colitis can acquire these infections and develop worsening symptoms. Recognising these infections is important, as the treatment for ulcerative colitis could worsen the infectious process.

In patients with diarrhea and adbominal pain, clues to the presence of ulcerative colitis in laboratory blood tests would include anemia and an elevated Erythrocyte Sedimentation Rate (ESR) or C-Reactive Protein (CRP). There are a number of so-called markers of colitis that can be detected in the stool and blood in patients with ulcerative colitis, but none are currently accurate enough to distinguish ulcerative colitis from other causes of bloody diarrhea

How is it treated?

The majority of patients with ulcerative colitis respond to conventional medical therapy; less than 20% need surgery to remove their colon (colectomy). Most patients will experience improvement in symptoms with medications taken by mouth, although those with disease limited to the rectum often do better with topical agents (enemas, suppositories). Only 15% require admission to hospital for intravenous medications, and this most commonly occurs shortly after diagnosis. For patients with mild to moderate disease, it is unknown whether being treated at an academic medical center or by a primary care physician makes a difference in treatment outcomes. With treatment, about 50% of patients remain in remission for periods of months to years. Figure 2 highlights the main therapies used in ulcerative colitis. They are described in detail below.


5-aminosalicylates (5-ASAs)
These agents include free 5-ASA, known as mesalamine (Asacol, Lialda, Pentasa, Salofalk), which is enclosed within special capsules that are designed to begin releasing the active drug at various locations along the small intestine or colon Other agents include 5-ASA bound to sulfapyridine (Sulfasalazine, Azulfidine),  to another 5-ASA molecule (Olsalazine, Dipentum) or a carrier molecule (Balsalazide, Colazal). Free 5-ASA is absorbed by the lining of the colon where it inhibits a number of key components in the initiation and maintenance of inflammation. Response rates of 70-80% have been reported in clinical trials, and the effect on symptoms may take up to 2-4 weeks to reach its peak. It is important that patients receive a sufficient dose, as its effects appear to be dose-dependent. In those who respond, these drugs are effective in maintaining the disease in remission. Mesalamine comes in an enema (Rowasa) and suppository (Canasa) form also, which is ideal for patients with disease limited to the lower third of the colon. For this group, topical mesalamine is as effective as, and possibly more effective than, oral mesalamine [3].
Side-effects from 5-ASA compounds are uncommon. The important one for patients to recognise is a worsening of their diarrhea, which occurs in 5-15% of patients, due to either an allergic-type reaction or an increase in the secretion of water by the small bowel. If diarrhea worsens once these agents are started, inform your physician. There are a number of rare serious side-effects such as allergic-type reactions in the pancreas, lungs, kidneys, skin and bone marrow. Reduced sperm counts have been noted with sulfasalazine (Azulfidine), so this should be kept in mind for men trying to get their partners pregnant. The majority of these adverse effects are reversible once the drug is stopped.

Steroids (Prednisone, Prednisolone
, Hydrocortisone, Methylprednisolone
)

Steroids are the usual next line agent if adequate doses of
5-ASAs fail to improve symptoms. They can be given by mouth, by rectum, or intravenously, depending on the location and severity of the disease. Steroids produce consistent responses in about 70-80% of patients within a week. Although suitable to calm down active colitis, they are not used in the long-term due to their serious side-effects. Once started, they are usually slowly reduced in dose over a number of weeks. This is to minimize the inhibition of production of the body’s own natural daily steroids in the presence of large doses of oral steroids.
The list of side-effects of steroids is a long one, and includes osteoporosis, diabetes, hypertension, cataracts, psychosis, acne, facial swelling, and increased risk of infections. Careful and conservative use of steroids should minimize these problems, although some patients are unable to reduce their steroids without a worsening of their symptoms, and become steroid-dependent. As ulcerative colitis itself confers a higher risk of osteoporosis, the addition of long-term steroids increases this risk.


Immunomodulators (azathioprine / 6-mercaptopurine)

Patients who require steroids usually need a more potent agent than
5-ASA to maintain remission. Azathioprine and 6-mercaptopurine fulfill this role, as they inihibit the inflammatory actions of some white blood cells. Both agents take about 8-12 weeks to inhibit the immune system, so steroids are often continued and slowly reduced during this time-frame. The most common side-effect in practice is nausea, but patients also need monitoring of their white blood cell count, and liver blood tests to screen for damage to white cells or the liver by these drugs. There is a genetic test available that may identify those at higher risk of damage to white blood cells, and it is possible to measure the level of the drug in the blood. On rare occasions, pancreatitis, lung fibrosis and drug rash may occur, and taking these agents does put patients at a higher risk of infections and certain cancers, especially lymphoma. On the other hand, azathioprine and 6-mercaptopurine improve the chance of remission by about two-fold, with remission rates close to 60-70% [4]. Each individual considering these agents should discuss the pros and cons with their physician.


Cyclosporine

Cyclosporine (Neoral) is used as “rescue therapy’ when patients with severe disease fail steroids and are facing surgical removal of the colon. When patients who require admission to hospital and intravenous steroids fail to improve within a few days, cyclosporine has been shown to obtain response rates of about 80%. It initially is given intravenously, and then orally. It is not used routinely in those with milder disease, as the side-effects of tremor, kidney damage, hypertension
, seizures and infections are significant. However, it can get patients over the severe episode of colitis and allow them to consider continued medical treatments or planned (elective) surgery.


Infliximab

Infliximab (Remicade) is an intravenous drug that has been used for 10 years in Crohn’s disease, as it binds to
the inflammatory protein Tumor Necrosis Factor alpha (TNFα) and reduces intestinal inflammation. Recent studies have shown it is also effective in ulcerative colitis, in those with moderate to severe disease. It is used similarly to cyclosporin, in those with severe disease facing surgery, but also in those with moderate disease who have failed other agents. It is not clear currently which is the “best” drug to use where steroids have failed and surgery is a prospect, so different centers use either infliximab or cyclosporin. The side-effects of infliximab usually occur in the form of reactions to the infusion. These can take the form of fevers, aches and pains or hives during the infliximab infusion (early), or similar symptoms a few days later (delayed). Many of these can be managed with antihistamines or  by slowing down the infusion. There is a small increased risk of bacterial infections, including tuberculosis, as well as rare risks such as heart failure, multiple sclerosis, lymphoma, and liver reactions. These risks are relatively low, but should be taken into consideration. Unlike cyclosporin, infliximab is routinely continued indefinitely every eight weeks in those who respond to it.

Antibiotics & Probiotics

When one considers that bacterial elements are a trigger for the intitial inflammation in ulcerative colitis, then manipulating colonic bacteria as a therapy makes sense. Rifaximin (Xifaxan) is a non-absorbed antibiotic that temporarily changes the mix of bacteria in the colon; in small studies, it has been shown to be effective in ulcerative colitis. It is a promising agent for those that have failed 5-ASA. There are no major side-effects, but it is unclear whether resistance by bacteria would become an issue in the long-term. Other antibiotics such as ciprofloxacin have shown some clinical benefits in ulcerative colitis, but are not routinely used.
Probiotics are
organisms, either bacteria or fungus, that promote beneficial effects in the colon. The normal colon contains billions of bacteria, which compete with other detrimental organisms for survival in the “pea soup” of the normal colonic flora [5]. Lactobacillus, Bifidobacteria, Saccharomyces and Streptobacillus are considered to have such protective properties. Single strains or combination of strains of some high-dose probiotics have been shown to produce similar results to mesalamine in inducing and maintaining a response in active ulcerative colitis. E.coli Nissle 1917, Bifidobacteria, Saccharomyces boulardii and a high-dose mix of Bififdobacteria, Lactobacilli and Stretptococcus (“VSL
#3”) had beneficial effects in clinical studies. However, many of the probiotics sold in stores and over the Internet have not been tested in ulcerative colitis, and may be at lower concentrations than those used in clinical studies.


Alternative Therapies

The agents listed above are considered standard medical treatments for ulcerative colitis. Clinical trials have found some benefits in a number of alternative treatments. They can be considered in mildy active disease if an alternative or addition to 5-ASA is desirable.
Both germinated barley foodstuff and psyllium (Metamucil, Fybogel) stimulate the growth of beneficial colonic bacteria, and have been reported to improve symptoms in mildly active disease. Aloe vera capsules were also shown in one study to be better than placebo (dummy pill) in improving symptoms in mild ulcerative colitis. Other agents that improve symptoms of ulcerative colitis include curcumin, tumeric, wheat grass juice,
Jian Pi Ling tablets, Kui jie qing enemas, acupuncture with moxibustion, and bovine colostrum enemas [6]. In addition, some patients report benefits with a restricted carbohydrate diet, known as the “Specific Carbohydrate Diet”. Most of these treatments have not been compared to placebo in measuring objective outcomes like colonic healing, which is considered the benchmark to assess any therapy.

Investigational treatments

Novel treatments for ulcerative colitis are currently under development or in clinical trials. All registered studies can be viewed without cost at
http://clinicaltrials.gov/. The novel treatments include:

- antibodies directed against specific types of immune cells (visilizumab, daclizumab, basiliximab)

- inhibitors of cytokine activity (RDP58, alicaforsen)
- inhibitors of migration of immune cells to the colon (MLN-02, ISIS-2302)

- pig worm ova (Trichiuris suis)
to influence the immune response

- removal of certain immune cells (like dialysis) from the circulation (Adacolumn)

- agents that work in a similar manner to 5-ASA (rosiglitazone)

Access to these therapies is currently only available through clinical trials as they are not F.D.A. approved
for ulcerative colitis.


What about surgery for ulcerative colitis?
Removal of the diseased colon is usually reserved for patients who have failed to respond to conventional medical therapy, or who develop cancer. The standard procedure is a total colectomy (removal of the entire colon) and either placing the small bowel draining to the skin (ileostomy), or formation of an internal pouch of small bowel (ileal-pouch anal anstamosis (IPAA). The surgery is relatively safe, and can be done by the keyhole method (laparoscopically). The early complication rate is less than 10%; the complications that do occur include infections, failure of the pouch and the usual risks of any major surgery, such as blood clots. If an IPAA is formed, the entire procedure may be performed in one operation or in two, depending on the severity of the disease during the initial surgery. Patients who have an IPAA typically have 4-7 stools per day, which is usually an improvement on their symptoms before surgery. Unfortunately about 15% of patients develop chronic inflammation in the new pouch (pouchitis), which is diagnosed and treated in the same manner as ulcerative colitis. Other long-term complications of an IPAA include irritable pouch syndrome, cuffitis, pouch cancer and reduced fertility.


What is the role of dietary factors in ulcerative colitis?


Many dietary factors have been implicated in putting individuals at higher risk of developing ulcerative colitis, but none can be definitiely said to cause the disease. Diets high in sugars, refined carbohydrates and fat – and low in fibre, fruits and vegetables – are more common in patients diagnosed with ulcerative colitis [8]. Whether this is because they have altered their diet because of the diarrhea, or whether the composition of their diet caused the disease is unknown.
Once ulcerative colitis is established, there is no specific diet that patients must adhere to other than a healthy, balanced diet. Many patients mistakenly restrict dairy products and fruit and vegetables in their diet, which can compound nutritional  deficiencies without any reduction in the risk of disease flares. Dietary fibre needs to be reduced only during flares when diarrhea is severe. Dairy products need only be restricted in those with known lactose intolerance, which is less than 15% of patients with ulcerative colitis. A number of nutritional deficiencies can develop in patients with active disease, including iron, folic acid, vitamin D, calcium, magnseium and vitamin K. Thus, it is important that patients have these checked and replaced either via diet or supplements.


What are the implications for fertility and pregnancy?


Women with ulcerative colitis who are planning pregnancy should discuss this with their physician. In general, women with ulcerative colitis that is under control have similar fertility rates and birth outcomes to women without this condition. Women experiencing fertility issues who have a male partner taking s
ulfasalazine should consider tests of sperm count, as this drug can reversibly lower sperm counts. There have been some studies that suggest men taking azathioprine or 6-MP have a higher rate of birth defects in their offspring, but this has not been convincingly confirmed.
The risk of a disease flare during pregnancy is similar to the non-pregnant population, and the risk of offspring developing ulcerative colitis is less than 5%. It is important to maintain the disease in remission for pregnancy, as there may be a higher risk of low birth weight infants in women with active disease, due to pre-term labor. Studies of women who were pregnant while taking either 5-ASA, azathioprine / 6MP, steroids, cyclosporin, or inf
liximab have not shown any increased risk of birth defects or detrimental birth outcomes. Thus continuing those medications, which are keeping the disease quiet, is important in women planning pregnancy.


What are the complications of long-term ulcerative colitis?

Long-term ulcerative colitis puts the patient at risk for or complicates a number of other conditions. The most common include disease flares, colorectal cancer, osteoporosis, and nutritional deficiencies.
About two-thirds of patients have a disease course characterised by mild disease controlled by medical therapy. The other 33% experience aggressive disease that requires intensive treatment, and about 15% end up in hospital needing intravenous steroids. The cumulative risk of a disease flare is 60-70% over 10 year. Patients with ulcerative colitis do not die at any higher rates than the general population. Although there is historically a higher risk of colorectal cancer for patients with ulcerative colitis, anti-inflammatory medication and surveillance colonoscopy can reduce this risk to close to that of the unaffected population. It is important that regular surveillance colonoscopy is performed every one to two years in those with more than eight years of disease, in order to detect early maligant changes in the colon. Patients with extensive disease, young age at diagnosis, a family history of colon cancer, and a diagnosis of primary sclerosing cholangitis have the highest risk of colon cancer in patients with ulcerative colitis. Thinning of the bones (osteopenia) occurs in about 25% of patients with ulcerative colitis, particularly those who have required steroid therapy. As a consequence, bone mineral density testing is recommended, and treatment with calcium and vitamin D or bisphosphonates is sometimes necessary.
A number of nutritional deficiencies can develop in patients with active disease, including iron, folic acid, vitamin D, calcium, magnesium and vitamin K. Fortunately these tend to occur only with chronically active disease, and improve once remission is obtained. Thus, it is important that patients have these checked and replaced either via diet or supplements.


Conclusion

Ulcerative colitis is an uncommon disease that is effectively managed in most patients with medical therapy. Although the exact cause remains unknown, many of the complications that can occur have been reduced by long-term medication use. Further research into the role of the interaction between bacteria and the human immune system may provide promising methods of preventing or treating this condition in the future.


References
  1. Vermeire S, Rutgeerts P. Current status of genetics research in inflammatory bowel disease. Genes Immun. 2005 Dec;6(8):637-45
  2. Farrell RJ, Peppercorn M. Ulcerative colitis. Lancet. 2002 Jan 26;359(9303):331-40.
  3. Moss AC, Peppercorn MA. Combined oral and topical mesalazine treatment for extensive ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol. 2006 May;3(5):290-3
  4. Timmer A; McDonald J; Macdonald J. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD000478
  5. Sartor RB. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics. Gastroenterology. 2004 May;126(6):1620-33
  6. Langmead L, Rampton DS. Review article: complementary and alternative therapies for inflammatory bowel disease. Aliment Pharmacol Ther. 2006 Feb 1;23(3):341-9.
  7. Metcalf AM. Elective and emergent operative management of ulcerative colitis. Surg Clin North Am. 2007 Jun;87(3):633-41
  8. Cashman KD, Shanahan F. Is nutrition an aetiological factor for inflammatory bowel disease? Eur J Gastroenterol Hepatol. 2003 Jun;15(6):607-13
Links
There are a lot of websites with information on ulcerative colitis, but many are simply selling or promoting a product, or have unverified information. The sites below provide reliable information for patients.
 
Crohn’s & Colitis Foundation of America
European Federation of Crohn's & Ulcerative Colitis Associations
Clinical trials conducted in the United States and around the world
National Digestive Diseases Information Clearinghouse (NDDIC) for patient information on ulcerative colitis
National Library of Medicine’s patient information page on ulcerative colitis
National Health Service (United Kingdom) – patient information on ulcerative colitis
Health On the Net (HON) – a United Nations resource for searching health-related websites that comply with a code of practice in distributing health information to patients