This article outlines the signs, diagnosis and treatment of common bowel disorders. We believe that this article will be of great help to anyone who believes they may be suffering from a bowel disorder or to those who have been diagnosed and would like to know more about their treatment options.
Contents
Introduction
The term Inflammatory Bowel Disease (IBD) generally refers to both Crohns Disease (CD) and Ulcerative Colitis (UC), which, as the name suggests are both chronic diseases involving inflammation of the gastrointestinal tract. Additionally around 5-10% of patients present with a colitis (inflammation of the colon or large bowel) that is difficult to diagnose as either UC or CD and can be described under the microscope as 'indeterminate'. Though there is much ongoing research we do not know the cause of these two conditions and subsequently cannot offer a 'cure' of either condition. As well as being bowel conditions, there can be associated inflammation of the skin, eyes and joints and there are also some associations with liver conditions. The causes of both diseases are multifactorial with genetic and environmental factors likely to play a role. The last decade or so has seen a great increase in our understanding of these diseases and the treatments which are effective, and increasingly the need for a multidisciplinary approach in their management. Both diseases have the potential for considerable social embarrassment and can have a profound effect on quality of life. In this article I will discuss both UC and CD in some detail with a focus on the treatments we can offer and also hope to answer frequently asked questions about the diseases and their management.
Prevalence and Incidence
As a rough estimate there are somewhere between 180,000 and 200,000 people in the UK with IBD, with an average sized UK hospital having 45-50 new cases per year with around 500 under follow-up (1). Of these around 60-80,000 will have CD and 120,000 have UC. The number of newly diagnosed cases is relatively stable although there is some evidence that the incidence of Crohn's may be increasing. The incidence of CD is around 5-10 per 100,000 per year with a prevalence of 50-100 per 100,000. This equates to around 1 in 1000 of the population. For UC the incidence is 10-20 per 100,000 per year with a prevalence of 100-200 per 100,000 which equates to about 1 in 500 of the population. Recent studies have demonstrated that there is a genetic component to both diseases. For UC, having a first degree relative increases the risk of developing the disease by 10-15 fold which equates roughly to a 5% risk. This does mean however that there is a 95% of not developing the disease and this should be emphasised. There is a similar 10 fold risk in CD, though this may be even higher in particular ethnic groups such as the Ashkenazi Jewish.
Ulcerative Colitis
Ulcerative Colitis is a chronic disease of inflammation of the mucosa (the skin lining the large bowel) of the colon. Generally speaking the inflammation is continuous and starts in the rectum, extending proximally into the colon to varying degrees (figure 1). Like CD, UC most commonly presents in younger years with a peak incidence between 10 and 40yrs. However, at least 15% of cases will present in the over 60.
Any cause of inflammation of the colon, especially infection, can cause diarrhoea and occasionally blood. Ulcerative colitis however will generally present with a chronic history of bloody diarrhoea which has not settled and this should always prompt investigation. People may sometimes find that their symptoms have been intermittent and occasionally the first attack is severe and requires hospitalisation.
Diagnosis
The diagnosis of UC is made with a combination of medical history, clinical evaluation and endoscopic findings (both by what the endoscopist sees and what the biopsies look like under the microscope). Endoscopically UC usually demonstrates confluent ulceration from the rectum proximally with an abrupt cut off to normal mucosa (see figure). Occasionally the rectum appears 'spared' and there are also some patients who have a 'patch' of inflammation at the beginning of the large bowel as well. A series of blood tests is taken. The clinician will be looking to ensure the blood biochemistry is normal, that the patient has not become anaemic due to bleeding or whether here are significant markers of inflammation in the blood. One of these markers, the C-Reactive protein, is particularly useful since in severe disease it becomes a good predictive marker of response to therapy. It is also vital that a stool sample is examined to rule out infection and increasingly to ensure that there is no infection including clostridium difficile.
If the attack of colitis is severe then a procedure called a flexible sigmoidoscopy (a form of endoscopy whereby a viewing instrument is inserted through the anus to examine the rectum) may be performed without any preparation to visualise the bowel and take biopsies. However, generally the investigation of choice is a colonoscopy which looks at the whole large bowel and the very end of the small bowel. This will demonstrate the extent of disease and also give the most information in terms of differentiating the disease from CD. The extent of disease can be defined by anatomical level into procitits (affecting only the rectum), left sided disease (to the level of the splenic flexure), extensive disease (affecting the proximal large bowel) or pancolitis (affecting the whole large bowel). The extent of disease is important as it dictates the type of treatment that is appropriate and also whether surveillance of the disease is needed in years to come.
Treatment
The type of treatment offered to patients with UC will depend on the severity and extent of disease. To a certain extent some of the therapies treating UC and CD are very similar but there are some particular differences in efficacy.
The first line of therapy in UC is a group of drugs called the 5-ASAs (5-Aminosalicylic acid). These are anti-inflammatory drugs that can be taken by mouth or per rectum and act directly on the bowel mucosa. There are many available which are broadly grouped by the mechanisms by which the drug is released: Azo-compounds (sulfasalazine, olsalazine, balsalazide), controlled release (Pentasa'), pH dependent (Asacol', Mesren', salofalk', claversal') or a composite (Mezavant'). Generally most are similarly effective. However the mesalazine based drugs tend to be better tolerated. The convenience of a once daily preparation (Mezavant') is a recent addition to the market.
For proctitis it is generally recommended that a 5-ASA suppository be the first line treatment since this gets treatment in the highest concentration to where it is needed (2). For left sided disease enema and oral 5-ASA may be needed with or without the addition of steroid therapy if needed. Extensive colitis and pancolitis are unlikely to respond to topical therapy alone and treatment and maintenance with an oral 5-ASA is advised.
Steroids such a prednisolone can be very effective in the short term in getting patients in remission but oral steroids serve no role in the maintenance of disease. Steroids can be given per rectally in suppository and enema form and tend to be as efficacious as 5-ASA treatment. In an attempt to avoid escalating treatment further some physicians may elect to use both 5-ASA and steroid topical therapies together. If the disease is moderately severe or is not settling then there is a role for oral steroid therapy and indeed, if the disease is severe and requires hospitalisation, intravenous steroid. Prednisolone will generally be started at a high dose of around 40mg and then decreased slowly (for example by 5mg each week), as decreasing the dose quickly or abruptly usually leads to relapse of disease. If a patient finds it difficult to decrease steroids without a relapse of symptoms or has a relapse quickly after stopping therapy then it is worth considering further immunosuppressant therapy.
The immunosupressants that have been used to treat UC include azathioprine, mercaptopurine, mycophenolate mofetil, ciclopsorin and methotrexate. The latter has been successful in some patients but I tend not to use this in my practice for UC patients since the evidence is weak. Ciclosporin is a highly effective drug in getting patients into remission with severe colitis (up to 80%) but due to its side effect profile has little role in chronic disease. Mycophenolate is sometimes used as a second line agent when others are not tolerated. The mainstays of therapy are azathioprine or mercatopurine. These are very similar drugs with the latter perhaps being better tolerated. They take at least 2-3 months to demonstrate any efficacy and are usually started therefore while treatment is ongoing to settle a flare of disease.
Azathioprine and mercaptopurine affect the way the white blood cells in the body function and hence there are a few side effects that need to be discussed prior to commencement of therapy. Some patients do not produce an enzyme that is needed to break this drug down which can make it potentially toxic (thiopurine methyl transferase or TPMT). Many units, including mine, will therefore check for activity of this enzyme before commencing therapy. This does not however completely protect against the rare side effect of suppressing the bone marrow so we tend to check the blood count every week for 6 weeks when commencing therapy and every 3 months thereafter. As with any immunosuppressant there is an increase also a small increase in risk of infection and a risk of becoming more unwell if infected with certain infections such as chicken pox for the first time. As part of normal practice I now check for chicken pox antibodies in the blood before starting therapy. (see frequently asked questions for further cautions with immunosuppressant drugs).
Biologic and other therapies in UC
There has been a huge explosion of the use of drugs called biologics in the treatment of inflammatory bowel disease. There is an established role in the treatment of CD (see later). In UC, infliximab has been used successfully in steroid dependent patients as a maintenance therapy and also as a rescue therapy for acute severe colitis that has failed conventional therapy to avoid colectomy. Unlike CD however the efficacy appears less than existing therapies, though it does remain an option.
Probiotic therapies in UC show promise but to date cannot be recommended as an efficacious therapy. Treatment with pig whipworm (trichuris suis) has been reported but only in a small study. There is some study evidence that aloe vera may be helpful in moderately active disease. Leucocytopharesis (washing out inflammatory blood cells form the blood) may have a role but its expense and potential complications may limit its use in the UK.
Surgery was previously the only effective treatment for extensive colitis. However, despite the better understanding of medical therapy, surgery still has a very important role in the treatment of UC. In fact deferring surgery in order to try yet more medical therapy in patients who are not responding to medical therapy may be detrimental. The mortality from elective colectomy for UC can be expected to be <1%, but figures rise to as much as 50% when surgery is carried out following bowel perforation in the immunosuppressed patient. It is therefore vital that when a patient is being considered for surgery the gastroenterologist works closely with a specialist colorectal surgeon to plan surgery at the appropriate time.
Generally speaking surgery is carried out for the following reasons: failure of medical therapy, severe colitis/toxic megacolon, findings of high grade dysplasia on biopsy (pre-cancerous cells) or colorectal cancer. There is now no place for segmental resection of the colon since the disease will recur and the cancer risk remains. Hence the operation will normally initially be a subtotal colectomy (removal of the colon) and ileostomy (bringing out the small bowel into a 'bag') with or without a plan to go forward for pouch surgery.
The ileoanal pouch involves fashioning a reservoir from the small bowel which is then anastamosed (joined) to the anal canal. This allows patients to be free of a stoma and for some gives a very good quality of life, though almost all will have some degree of stool frequency. Unfortunately however around 50% of patients can develop an inflammatory condition of the pouch called pouchitis. This can lead to urgency, frequency and abdominal cramping and usually responds to a combination of antibiotics, typically ciprofloxacin and metronidazole. For a few patients however the condition remains difficult to treat. An additional problem with pouch surgery in young women is that it has been demonstrated to increase the risk of infertility around 3 fold following surgery.
Colorectal Cancer risk and UC
Colorectal cancer (CRC) is a common disease affecting between 1 in 20 and 1 in 25 of the population in the UK. Patients with longstanding UC have a higher risk of developing CRC than the average population. The degree to which the risk is increased is debateable but evidence would suggest that the risk is highest in those with extensive colitis and intermediate in those with left sided disease, with proctitis only demonstrating no increase in risk. The risk is compounded by patients with an early onset of disease and those with associated primary sclerosing cholanigits (a disease of the liver associated with IBD). Current guidelines suggest therefore that in extensive disease a screening colonoscopy is carried out after 8-10 years with multiple biopsies and every 2 years thereafter. In patients with PSC we would offer annual screening from the diagnosis. There is some evidence that early changes in the cells can be noticed more easily by using dye spray to coat the colon and for these procedures I perform this routinely.
Crohn's Disease (CD)
Unlike UC, Crohn's disease can affect the whole gastroinetestinal tract from mouth to anus and also unlike UC can be a transmural process (affecting all levels of the bowel wall) with typical findings when tissue is examined under the microscope. Most commonly it affects the end of the small bowel (terminal ileum) and colon. As mentioned, we do not know the cause of the disease and the findings of certain groups of cells on biopsy (granulomata) have led to various theories about its cause, such as being secondary to a strain of tuberculosis or indeed to the measles virus or vaccine. However, none of these theories has been substantiated. The cause of the disease is likely to be secondary to both genetic and environmental factors. There is for example much more CD in Northern European than Southern European countries, although this appears to be changing in recent years.
Due to the nature of the disease, CD can be a debilitating disease with abdominal pain and weight loss being features in over 60% of patients and blood or mucous being seen in the stool in around 50% (3). Inflammation around the anus can cause fistulation (tracts communicating bowel with skin or other internal organs) which can lead to a great deal of discomfort. Ongoing inflammation in the bowel can also cause structuring, leading to blockages and indeed fistulation out of the bowel itself. There is however a wide spectrum of disease and it should not be forgotten that there are many people with Crohn's disease who lead normal lives and are relatively untroubled by their disease.
Diagnosis
Like UC, the most common presenting feature of CD is chronic diarrhoea. However, a proportion of patients present with predominantly abdominal pain and some with rectal bleeding or a combination of all of these symptoms. It is unusual to present with no bowel symptoms at all, but there may be associated symptoms outside the bowel, known as 'extra-intestinal' manifestations. These include joint pains, skin rashes and occasionally ulceration, liver abnormalities and sometimes red, gritty eyes. All of these have been described in IBD and are secondary to well-described conditions associated with the diseases. A patient will be asked about all of these when they are first seen. Interestingly around 10% of CD diagnoses will be changed to UC within the first year based on the clinical course and subsequent endoscopic imaging.
Like UC, endoscopic imaging is very important in establishing the diagnosis of Crohn's disease. In children, where upper gut CD is more commonly seen this will involve both upper and lower GI endoscopies with multiple biopsies. In adult practice it is more common to perform only a colonoscopy (figure 2) unless the patient presents with symptoms consistent with possible upper gut involvement. At colonoscopy it is important to inspect the terminal ileum since this is a common area for CD.
For many years the barium study, where contrast has been swallowed and X-Rays taken following the contrast down has been the gold standard for imaging the small bowel. However, this has very much changed in recent years. Though we still very much use what is known as 'the barium follow through', other imaging modalities such as the CT scan and MRI studies are becoming increasingly available. We can now also perform a capsule endoscopy, a procedure that allows us to inspect the whole small bowel. This involves swallowing a pill which has within it a camera that sends images back to a disc for us to analyse and has become a very useful tool in finding out exactly how much bowel is affected. In the future this may even dictate the treatments we use, though this is not yet clear.
The blood tests and stool cultures we carry out will be similar to those listed above with particular reference again to the CRP (see above). There is often anaemia present, and this can be secondary to chronic inflammation, iron deficiency or sometimes vitamin B12 deficiency if the patient has disease of the terminal ileum or indeed has had a resection of that area. It is always important to exclude infection and stool samples will be sent.
Some units will additionally use white cell scans which give a non-invasive idea of the distribution of inflammation. This however is not specific and I tend not to use the test.
Treatment
Once the extent of disease has been ascertained the treatment can be tailored accordingly. Many of the drugs used to treat CD are the same as those described for use in UC, though there are very particular differences in their use. The first management step in smokers is to tell them they must stop smoking. Smoking definitely worsens outcomes of therapy in CD and stopping smoking is extremely important.
Unlike in UC, there is evidence that liquid diets, either polymeric or elemental (food groups broken down to constituent elements) can act as treatment in CD and in some can be as effective as steroids. In children, these liquid diets can be very effective and avoid the need for drugs and subsequent side effects. However their use is somewhat limited in adult CD since they are very difficult to stick to and once stopped the disease often relapses. That said, liquid diets definitely have a role to play and can be extremely useful in relieving symptoms, particularly in complicated small bowel disease in which other therapies are failing.
The use of 5-ASA medication is more limited in their efficacy in Crohn's disease. For isolated disease affecting the terminal ileum there is limited evidence that they are helpful, although they are probably more so in colonic disease. They can still be used affectively for procitits in suppository form however. Certain preparations may have a role in small bowel CD and their favourable side effect profile means that we will often use them as a therapy.
Perianal CD particularly can be associated with sepsis and antibiotics are sometimes very effective in this setting. Hence ciprofloxacin and metronidazole are commonly used. There is also evidence that metronidazole may help prevent post-operative recurrence of CD, but the side effect profile after taking this drug continuously for a long time means we do not employ this strategy.
For many years steroids in the form of prednisolone were the mainstay of therapy for CD. However we now know that there is not good evidence to support chronic use in terms of maintaining remission and that the side effects and complications are problematic. Prednisolone is often used when patients have a flare-up of their CD to get the patient into remission and can be used safely for short periods. However chronic use can cause multiple side effects including weight gain, hypertension, impaired glucose tolerance (and diabetes in the susceptible), and worsen the risk of osteoporosis (which is already higher in CD). A newer type of steroid, budesonide, is less effective, but has much less in the way of systemic side effects. This has been shown to be effective in treating in CD and we would use it particularly in patients with terminal ileal CD in whom it appears to be particularly effective.
The use of azathioprine and mercaptopurine is well established in CD and is now used much earlier in the course of disease. There are obviously side effects of these drugs (see above) but their use has in some studies led to a period of sustained remission in up to 70% of patients and subsequently they tend to be used relatively early in the disease if problems arise. Unlike in UC, there is also a good evidence base for the use of methotrexate, which I tend to use as a second line in the azathioprine intolerant patient. There is some evidence for the use of ciclosporin in high doses for fistulating disease but generally the high doses and side effect profile at these doses mean that I do not use the drug in his situation, especially since other more effective treatments have become available.
The use of biologic therapy in CD has increased exponentially in the last few years. Infliximab is the most commonly used and is an antibody against an inflammatory molecule in the body called tumour necrosis factor. Hence this sort of drug is known as an 'anti-TNF therapy'. In the UK, infliximab is generally used in patients with fistulating disease and those in whom other therapies have failed. This approach however has been challenged in recent years. The suggestion is that if infliximab is used early in the disease then perhaps it will change long term outcome, although this has not been conclusively demonstrated. It can however be highly effective for some patients and is considered in all those with severe disease. Like any drug that affects the immune system, there are however possible serious side effects that have to be addressed. Recently there have been a few cases (in the hundreds of thousands of patients who have received the drug) of an aggressive type of lymphoma (blood cell cancer). Generally however, the lymphoma risk is felt to be around 4-fold (which is similar to azathioprine). This is however still very rare as lymphoma is a rare disease. We also check thoroughly for any evidence of tuberculosis before commencing therapy since this can reactivate following therapy.
The treatment is given as an induction course at 0, 2 and 6 weeks in the form of an infusion and if maintenance infusions are required then they are done so 8 weekly. It has been shown to be more effective in a very recent trial than azathioprine alone in patients who have not previously had an immunosuppressant. There are now two other anti-TNF therapies available in the UK ' adalimumab and certolizumab. These are both injectable forms and can therefore be given by injection outside the hospital environment after initiation. Early studies show promising results. Generally they tend to be used more as second line therapies due to our comparative experience with infliximab, though this may change as more evidence is available. There are other biologics that have been used but I have not reviewed them here since none has been evaluated for the maintenance of CD.
Probiotics, fish oils, leucocytapheresis (see above) have all been trialled and to some extent have demonstrated some positive findings. There is great interest in the use of prebiotics as the concept of changing one's diet for treatment of CD is clearly very appealing. It is thought that if this effective it is in changing the bacterial flora and remains the subject of ongoing research.
Surgery for UC is described as curative, since the whole colon is removed. However, since CD can affect the whole gastrointestinal tract this is not the case for CD. As with all IBD, surgery should be discussed between the gastroenterologist and specialist colorectal surgeon as early as possible and planned accordingly. Surgery is often carried out for isolated terminal ileal disease with a limited resection and anastamosis. This is often highly successful with only around 50% of these patients coming to further surgery. However if one looks endoscopically at around a year, up to 70 % have some recurrence at the surgery area, and at 5 years this is probably as high as 90%. There has been much debate therefore as to how CD should be treated post-operatively, and this is not clear. In my practice this will always be after discussion with the patient and if there have been complicated problems prior to surgery I would usually advise staying on a drug such as azathioprine post-operatively to try and minimise the chance of recurrence.
Surgery may also involve the treatment of strictures which can either be resected or treated if possible with 'stricureplasty' which involves opening up the bowel segment. The surgeon will always try and preserve bowel where possible since if too much bowel is resected then 'short bowel syndrome' can develop in which not enough bowel is left to absorb fluids and nutrients. Perianal disease is often treated surgically to relieve areas of infection or to lay open fistulae to allow them to drain and heal. In this situation it is very important that the team work together to improve the post-surgical outcomes.
When colectomy or removal of the rectum is necessary in CD we do not recommend a pouch operation (see above). Unfortunately, the pouch operation in CD patients is associated with poor outcomes and is not advised.
Colorectal Cancer risk and CD
Currently we generally offer screening to those who have extensive colonic CD after 8-10 years although the degree of increase in risk in this population is not clear.
