Ibd Reviewing The Ibd Patient Biology Essay
Inflammatory bowel disease is a condition which is commonly characterised by two separate entities; Crohns Disease and Ulcerative Colitis. This essay will closely look at the two and discuss the differences between them and their management.
Both forms of inflammatory bowel disease have similar features and they primarily affect the proper functioning of the gut or intestinal lining.
This review will go into detail about the epidemiology and aetiology of the disease as well as focusing on the pathological characteristics of the different conditions. Attention will also be given to how different patients such as the paediatric patient and the pregnant patient deal with the disease and how treatments differ within them.
Epidemiology and Aetiology
Epidemiological studies focus on the prevalence and incidence rates of diseases where prevalence shows the number of people in the population who carry a disease and incidence shows the rate at which a disease arises in a given area. For IBD, different areas of the world will be discussed to distinguish the differences between given populations.
Inflammatory bowel disease can be classed as a new generation disease. It has come mainly into the developed world . Figures given from Shanahan and Bernstein  show that in the USA alone up to 1.5 million residents have either CD or UC. In North America, studies conducted by Loftus et al  show that for CD alone, in every 100,000 cases, an upper end figure of 198.5 cases are reported. From the estimated population of 340million in North America , there are 400-600,000 patients with diagnosed CD, which equates to between 9000 - 44,000 new cases present per annum .
Graph 1  shows that the incidence of Crohn's disease in the years shown is generally on the rise. However some cases show that the incidence has dropped. In Cardiff the incidence in 1985 was 80million per year yet by 1990 it has fallen to 60million per year.
As discussed previously IBD is a disease which generally affects developed population and this is evident from the locations given in the graph above.
Graph 2  shows a similar trend to Crohn's disease however there are more fluctuations in the incidence rate. The male population in Rochester (USA) shows a great variation in the incidence rates where in 1979 a rate of 70million per year was recorded. By 1985 this had risen to 110million and by 1989 it had dropped again to 80million. However the female population in Rochester (USA) does not show such large changes in the incidence rates.
The aetiology of a condition describes the causes and how the disease originates. Although the exact cause of IBD is unknown, genetic, environmental and immunological factors give a solid starting point into researching the cause .
The immune system is thought to have a large input in both diseases. Immunologically both diseases are T-cell driven which have various cytokine interaction and under unwanted circumstances, the cells are activated which lead to the inflammation . The gut, in a normal case has flora which is not harmful. Flora contains the many microorganisms which live in the intestine. It is thought that gut flora is commensal meaning that it a non harmful existence but it can provide some benefit in terms of training the adaptive immune system and protection against harmful growth of bacteria . In disease, gut flora is possibly thought to become a genetically vulnerable host because the immune system has developed a dysregulation in its normal function .
Genetic factors are important in understanding the reason why the symptoms of IBD occur. These factors are present in both CD and UC but are clearly shown in CD. The break-through in distinguishing susceptibility genes led to conformation that CD and UC are related but are distinct, separate disorders . The gene, NOD2 (also known as CARD15) has been associated with CD. NOD2/CARD15 gene activates a transcription factor called NF-kB which causes an immunologically related inflammatory response, hence producing pro-inflammatory mediators . Other genes are now being identified to have an association with IBD which may cause cell death, however studies do not show complete evidence of this 
In terms of the specific aetiology of UC, it is underdeveloped in comparison to CD. As discussed, microflora present in the gut can become genetically susceptible  however for UC; there is not yet a microorganism which can be individually identified for the development of the disease . The inflammation occurring in the colon during UC is thought to present itself due to the abnormalities in the immune system which in turn fight against the enteric bacteria and subsequently lead to inflammation.
When focusing on the pathophysiology of IBD (inflammatory bowel disease), the cause of the symptoms of the conditions need to be explained. The main cause of the symptoms of both conditions is inflammation of the intestinal wall and colon.
Key molecules involved in the explanation of the symptoms of both conditions are cytokines known as interleukins. An interleukin (IL) is a group of proteins which fall under the cytokine category. They are made from leucocytes to regulate the immune system. Many forms of these exist, however when considering UC and CD, primarily IL-1, IL-6, IL-8, IL-10 and IL-12.
To understand this process in more detail, the role of the immune system must be explored further. When considering the inflammatory response, the cells which modulate it such and B cells and T cells play an important role. B cells produce antibodies which travel through the serum to attack antigens. In IBD, it is the T cells that play a greater role. T cells are further categorised into T helper cells which recognise antigens to either stimulate B cells or to produce cytokines and T killer cells which destroy any antigen presenting cells. As mentioned, interleukins and other cytokines such as tumour necrosis factor (TNF) and interfon gamma (IFN-Î³) are produced by the Th (T helper) cells which have a surface protein known as CD4+ T cell which acts to regulate the function of the Th cell itself. Th cells can be subdivided into many, namely Th1, Th2, Th0, Th3, Thp and Tr1. With IBD, the main imbalance is caused between Th1 and Th2. It is these subdivisions which secrete the specific cytokine. Th1 secretes IL-2, IFN-Î³ and Th2 cells secrete IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13  The Th2 response which produces the majority of the interleukins involved mainly act on the mucosal intestinal areas whereas Th1 response favours the intestinal cells. From this information, it can be said that the Th2 response is more commonly presented in UC as it is the mucosal lining of the colon which becomes inflamed and the Th1 response is therefore seen in patients suffering from CD 
The Th1 inflammatory response is also known as delayed-type hypersensitivity (DTH) which acts as the first defence against infectious agents. It is this protective defence mechanism that releases the proinflammatory cytokines such as TNF, IFN-Î³ and specific interleukins. The cycle involved in DTH must be carefully controlled because the release of the Th1 response mediators may cause damaging effects on tissue, which then depends on ordered destruction of antigens. In instances where this regulation fails, inflammation develops which is what is thought to be the primary onset of the inflammation observed in IBD. 
This image shows the natural immune response to enteric antigens in the intestine. Here you can see that the cytokines may affect the epithelia of the gut to release large amounts of proinflammatory mediators. 
Albeit, CD and UC are under the umbrella term of inflammatory bowel disease, they still present with some different symptoms and treatments plans for the two conditions vary.
UC is a condition which mainly affects the mucosal lining of the colon and usually only extends as far as the rectum . The main symptoms observed in UC include:
Frequent loose bowel movements
Bloody or mucous stools
Urgency to empty bowels
Lower abdominal discomfort or pain
Lack of energy
CD on the other hand can occur spontaneously or sporadically anywhere along the whole alimentary tract but is usually found to affect the bowel wall, namely the terminal ileum. The main symptoms here are similar to those described above for UC, however in CD; the following may also be presented :
Non bloody diarrhoea
Postprandial bloating (feeling of over-fullness after eating)
Tender mass/cramps in lower quadrant
One common and distinctive symptom seen in both conditions is diarrhoea. The presence of inflammation makes the symptom of diarrhoea prominent in both conditions. The pathophysiology behind the mechanisms responsible lead to choosing the correct treatment plan. In CD, the mechanism is more complex since both the small and large intestines are affected, therefore there are more mechanisms involved .
Figure 2 shows how general overall absorption occurs. As summarised above, approximately 8L of secretions and dietary intake enter the small intestine. Only around 6L of fluids are absorbed by the small intestine, whilst the rest is classed as being the ileo-cecal (rate of flow from ileum to caecum) flow as suggested from studies . The large intestine also has absorptive qualities where almost up to 5L of fluids are absorbed. If absorption in the small intestine is reduced then the ileo-cecal flow increased causing diarrhoea, whereas if the flow was less than the maximal absorptive capacity of the colon then no diarrhoea would occur. Subsequently if the small intestine did not absorb any of the fluids which entered, then diarrhoea would occur at a significant rate. This explains the main underlying principle behind the mechanism of diarrhoea however in both CD and UC, many ion absorbing systems may alter the regulation of the process.
Quality of life is an important factor when discussing IBD. A study which measures the health-related quality of life (HR-QOL) can be conducted to measure how it affects IBD patients. This study is conducted by using a wide range of questionnaires which included many factors that were made to assess both the physical and psychological aspects of the diseases. A valid questionnaire that is commonly used with IBD is the Inflammatory Bowel Disease Questionnaire (IBDQ) which attempts to measure the bowel, systemic, emotional and social symptoms for the patient. This particular study works on a numerical scoring process where a higher score indicates a better quality of life. With reference to UC, the different factors which may influence the quality of life in these patients may be due to both social and emotional factors such as inability to attend school or work, sustain relationships and feeling angry or embarrassed may also be contributing factors that lead to poor quality of life. Literature suggests  that CD patients have a poorer quality of life than UC patients. CD also uses the IBDQ to measure quality of life; however the Crohn's Disease Activity Index (CDAI) also supports the assessment of quality of life in CD patients. The CDAI works by judging the symptoms by weighting factors. For example, abdominal pain may be given a weighting factor of 5, and then together with all the other symptoms each one is weighted and calculated. A value less than 150 indicated remission of disease.
It can be suggested that urgency as a symptom affects the quality of life in patients. In IBD patients, urgency can be described as feeling the need to empty the bowels as soon as possible  and in day to day life this may prove to be difficult. The sensation of urgency may deteriorate as disease develops. A possible cause of this may be that due to the fact the bowels are opened more frequently than non IBD patients therefore the tissue lining the rectum may become scarred so it may be difficult to stretch when the stool enters here 
As well as the symptoms, secondary diseases can also occur in IBD. These can occur at any time however secondary manifestations usually occur one year after diagnosis depending on the extent of the relapses. Table 1 below  shows the incidence rates of the different secondary diseases which can occur in IBD. Ophthalmic and musculoskeletal problems seem to be the most common and other literature supports this [5, 27].
Table 1  - Extragastrointestinal manifestations of inflammatory bowel disease (percentage of cases)
Treatments and Pharmacological Agents
IBD usually requires a range of treatments to keep the diseases in remission. Both conditions use similar pharmacological agents as treatments which usually include immunomodulators or immunosupressors and 5-aminosalicylic acids (5-ASA). When disease is considered to be in relapse, corticosteroids may also be administered. Both oral and topical treatments are used in these diseases and there a wide range of different agents which are useful. Treatment regimes are usually designed to target the acute disease which will then be followed by long term management to ensure remission .
The initial therapy given to IBD patients is usually a 5 ASA drug. It works by targeting inflammation in the bowel to reduce it. 5 ASA's consist of Sulfasalazine and Mesalazine. Mesalazine quoted by the BNF March 2009 has various drugs within it such as Asacol, Ipocol, Pentasa and Mezavant (brand names) whereas Sulfasalazine has its own entity.
Sulfasalazine is made up of a sulfa pyridine, linked by an azo bond, to the 5 ASA molecules which is the main functional group. Once the drug is administered, the azo bond breaks down by reductase enzymes to form sulfa pyridine and 5 ASA separately . Side effects of Sulfasalazine include loss of appetite, fever, kidney reactions such as proteinuria and blood disorders such as megoblastic anaemia .
Mesalazines are newer compounds which have a slow release action and since they have fewer side effects, they can be used in greater doses as treatment. Mesalazine compounds generally consist of two 5 ASA molecules and these are broken down by colonic bacteria.
5 ASA's are more common in the treatment of UC than CD . There are many mechanisms involved in the action of 5 ASA's and it is thought that they work by inhibiting pro-inflammatory mediators such as interleukins and TNF- Î± . Mesalazines can be administered both orally and rectally. Rectal treatment is preferred when inflammation is prominent in the distal colon. Caution should be taken when giving aminosalicylates as renal function may become impaired and nephrotic syndrome may occur as a side effect. Other side effects with Mesalazines include nausea, vomiting, headache and skin reactions such as lupus .
Alongside 5 ASA's, immunosuppressive drugs are also given as common treatment for IBD. They act by preventing lymphocyte production in the first (induction) phase of the immunological response  or by inhibiting the genes coding for several interleukins, particularly those involved in IBD. The main drug(s) which inhibit lymphocyte proliferation include Azathioprine and Mercaptopurine (6-MP) which is the metabolite for Azathioprine. Azathioprine is a common drug used in both CD and UC, but is generally more prevalent in UC. The drugs, known as thiopurines, work by inhibiting purine or pyramidine synthesis  which in turn ceases the production of lymphocytes. An important factor which must be considered when taking this drug is the need for regular blood monitoring. The enzyme which metabolises Azathioprine is thiopurine methyltransferase (TPMT) and when the activity of this enzyme is low, a condition known as myelosupression may occur which leads to fewer red blood cells, white blood cells and platelets.
Other drugs which are well established in treating IBD include Infliximab, Methotrexate, Tacrolimus and Ciclosporine.
Infliximab is a new generation therapy  and it is classed as a TNF-Î± antagonist . The mechanism of action of Infliximab works by binding to the TNF-Î± which is a pro-inflammatory mediator. The binding of Infliximab to TNF-Î± causes upregulation of other pro-inflammatory mediators and as a result apoptosis is induced . Infliximab is predominately used in CD and is given intravenously as it cannot be administered orally because certain digestive enzymes would destroy the drug Side effects of Infliximab include chest pain, fatigue, dyspnoea and various other which may be less common.
Methotrexate (MTX) has a similar effect to Azathioprine however it is more widely used in CD than UC. Since the mechanism of action of MTX involves preventing DNA synthesis, it can in turn stop the production of pro-inflammatory mediators. MTX is a drug which needs to be monitored in terms of whom it is distributed to. It displays embryo-toxicity meaning that one of its contraindications is women who are planning pregnancy .
Ciclosporine is a drug which has shown to be effacious with a severe relapse of UC. It is also an immunosuppressant which prevents the action and production of interleukin 2 (IL-2)  by inhibiting calcineurin. Although Ciclosporine is effective in treating sever UC, it come with many unwanted effects which in turn may limit its use. Ciclosporine is mainly used when response to corticosteroids is low. The most common side effect is neprotoxicity which is where a toxic effect caused by substances occurs in the kidneys causing malfunction .
A treatment regime which is often used in IBD but is not preferred is the administration of corticosteroids. Since steroids are used anti inflammatory drugs, they can be used acutely to manage flare-ups. The most common drug used for UC is Prednisolone and for CD it is Budesonide . Both drugs, when in severe relapse, can be given intravenously however they can also be taken orally. In cases where disease is limited to the rectum in UC, topical steroids may also be given. The dosage is usually reduced on a weekly basis until it is completely weaned off as it is dangerous to stop them suddenly . Steroid patients are often given a "Steroid treatment card" which informs health workers that the patient is on steroids should an emergency occur .
The side effects of steroids often make health professionals apprehensive about using them as first line treatment . In paediatric patients especially the over-use of steroids can lead to stunting of growth from an early age . Side effects of steroids range from gastro-intestinal effects such as dyspepsia and abdominal distension; endocrine effects for example hirsutism, weight gain and menstrual irregularities; neuropsychiatric effects such as insomnia and psychological dependence; musculoskeletal such as osteoporosis and ophthalmic conditions such as glaucoma and increased intra ocular pressure .
At present, there is no known cure for IBD without intervention surgery; it can therefore only be managed through drug therapy. Surgery however, does occur when both conditions are unable to enter a state of remission. In UC, surgery is curative and eliminates the risk of cancer associated with IBD , whereas in CD there may be risks of the disease returning and the likelihood of surgery is higher.
Surgeries which are general to both CD and UC are subtotal colectomy and ileo-rectal anastomosis. A subtotal colectomy is where part or the entire colon is removed without the removal of the rectum . An ileo-rectal anastomosis is where the rectal lining is removed so the ileum attaches to the anus and a pouch is made from the ileum to hold faecal material .
In recent years, it has been postulated that Non-steroidal Anti-Inflammatory Drugs (NSAIDs) can cause exacerbation of IBD . This hypothesis has not been completely confirmed however the mechanism by which NSAIDs act can suggest why these exacerbations may occur.
The main mechanism of NSAIDs is through the inhibition of cyclooxygenase enzymes (COX-1 and COX-2) which are used in the formation of prostaglandins (pro-inflammatory mediators) . The two enzymes are expressed at different levels where COX 1 is more abundant than COX-2 because it is the COX-1 enzymes which catalyses the prostaglandins . Current hypotheses' suggest that NSAIDs are toxic to the small intestine and colon because the by-products of the drugs may travel from the upper gastrointestinal tract to the colon and cause injury to the mucosa by mechanisms which are unknown [27, 29].
It has been recently studied that probiotics can aid in the prevention of CD and UC. Probiotics are living microorganisms which can contribute to a healthier lifestyle . The immune response is vital in understanding why pro-inflammatory arise. Since it is postulated that inflammation occurs because the immune system is under attack by normal gut flora, beneficial bacteria (probiotics) can be introduced to change the type of bacteria in the gut and alter the immune response . Lactobacillus species and Bifidobacterium species are the most common probiotics known for IBD. They may relieve symptoms by fusing to the intestinal wall which prevents harmful pathogens becoming recognisable. They can alter the pH of the gut by producing lactic acid which may be an unfavourable environment for the pathogens [38, 39]
Differences within patients
The different aspects discussed are general to a patient suffering from IBD, however certain patients such and paediatric patients and pregnant women may display different characteristics particularly with treatment regimes.
A particular cautionary factor which must be considered when treating childhood IBD is the over-use of steroid treatment. Since adverse effects of steroids include growth suppression, osteopenia which is a precursor to osteoporosis and infections are they should be administered with great care [32, 33]. The quality of life in children may also present differences whereby poor nutrition may lead to being underweight and this may have an effect on educational life as the child may feel less active .
Evidence does not suggest that IBD affects pregnancy any more so than a female without IBD. However some research has suggested that the influence of pregnancy may cause low birth weight with can in turn lead to adverse outcomes in cognitive function . Since there are potential undesirable effects, a pregnant patient who has diagnosed IBD should be monitored as a high-risk patient to insure a healthy pregnancy.
5 ASA's, immunosuppressants in particular Azathioprine, corticosteroids are all classed as being safe during pregnancy. Drugs which should not be given include Methotrexate and Ciclosporine. Methotrexate is a drug which is also used to induce abortions therefore if it is administered for IBD, it should be stopped immediately . Ciclosporine should also be avoided since it may cause fetal growth impairment and have toxic effects on female's renal function . A common problem encountered with pregnant IBD patients is the anxiety of the female taking drugs for continued remission in the fear of the drugs' affecting the fetus .
In conclusion, IBD which is further classified into two separate diseases known as Crohn's Disease and Ulcerative Colitis. They are diseases which affect the intestinal mucosa primarily by activating pro-inflammatory mediators and can range in affecting the entire gastrointestinal tract or limited to the colon. Drug therapies, both pharmacological and alternative for the conditions are similar however some pharmacological agents are better suited for the separate diseases. Particular attention must be given when dealing with paediatric and pregnant patients as disease activity may differ.
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