Environmental

Genetic

Fifteen percent of first degree relatives have IBD. There is mounting evidence that Crohn’s disease and ulcerative colitis result from an inappropriate response of the immune system in the mucosa of the gastro-intestinal tract to normal enteric flora (Ahmad et al., 2004). Since the mid-1990s there has been considerable progress in understanding the contribution of genetics to IBD susceptibility and phenotype.

Mutations of the gene CARD15/NOD2 located on chromosome 16 have been associated with small intestinal Crohn’s disease in white but not oriental populations. Two other genes have been recently linked with Crohn’s disease (OCTN1 on chromosome 5 and DLG5 on chromosome 10).

Genetic studies in ulcerative colitis have shown human lymphocyte antibody (HLA) is more strongly linked. Genotype related to pattern of disease (HLA-DRI’103) is 5–11 times more common in patients who have undergone colectomy.

Disease location

The character and distribution, both macroscopic and microscopic, of chronic inflammation define and distinguish ulcerative colitis and Crohn’s disease. Table 13.1 shows the differences in location and distribution of ulcerative colitis and Crohn’s disease. Figure 13.1 details the histological differences.

Table 13.1 Location and distribution of ulcerative colitis and Crohn’s disease

Fig. 13.1 Histological features in the rectal biopsy that help to distinguish between ulcerative colitis and Crohn’s disease

(from Misiewicz et al., 1994, with kind permission from Blackwell Scientific Publications, Oxford).

Crohn’s disease

The clinical features of Crohn’s disease depend largely on the site of the bowel affected, the extent, severity and the pathological process in each patient. Crohn’s disease tends to be more disabling than ulcerative colitis with 25% of patients unable to work 1 year after diagnosis. The predominant symptoms in Crohn’s disease are diarrhoea, abdominal pain and weight loss. Weight loss occurs in most patients, irrespective of disease location. Ten to twenty percent of patients will have weight loss greater than 20%. The main cause is decreased oral intake, although malnutrition is also common. There is a slight increase in mortality in patients with extensive Crohn’s disease.

Stricturing Crohn’s disease

Patients presenting with pain, vomiting and constipation and a diagnosis of stricturing disease can lead to perforation if not surgically treated, although this is rare (see Fig. 13.2)

Fig. 13.2 Stricture formation in Crohn’s disease.

Ulcerative colitis

Typical symptoms of ulcerative colitis include bloody diarrhoea (the most predominant symptom) with mucus, abdominal pain with fever, and weight loss in severe cases. The typical appearance of a patient diagnosed with Crohn’s disease is low BMI, malabasorption, weight loss and growth retardation. Frank blood loss is more common in ulcerative colitis than Crohn’s disease. The symptoms of ulcerative colitis are similar to Crohn’s colitis with patients being tachycardic, anaemic, febrile, fatigued, dehydrated and thin. Approximately 50% of patients with ulcerative colitis have some form of relapse each year, and severe attacks can be life-threatening. Up until the 1960s, one-third of ulcerative colitis patients died from the condition; with advances in medical and surgical treatment death is now extremely rare.

Extra-intestinal complications of IBD

Around 20–30% of patients with IBD will present with extra-intestinal manifestations. They are more commonly seen in patients where IBD affects the colon. Complications affect the joints, skin, bone, eyes, liver and biliary tree and are more common in active disease. Figure 13.3 highlights some of the extra-intestinal features of IBD.

Fig. 13.3 Some of the extra-intestinal illnesses and features of malnutrition found in patients with inflammatory bowel disease

(from Misiewicz et al., 1994, with kind permission from Blackwell Scientific Publications, Oxford).

Endoscopy

The key diagnostic investigation in IBD is lower gastro-intestinal tract endoscopy (sigmoidoscopy and colonoscopy), which allows direct visualisation of the large bowel and histopathological assessment from biopsies. The risk of developing colorectal cancer is 7–10% after 20 years in patients with colonic disease. Therefore, routine surveillance colonoscopy is essential in the early detection of colorectal cancer. Treatment response to biologics, for example infliximab, can be assessed via mucosal healing seen at colonoscopy.

In patients with severe symptoms, it is sometimes necessary to delay a full colonoscopy because of the increased risk of perforation. Wireless capsule endoscopy is a relatively new procedure where the small bowel can be viewed and can be useful in patients with non-stricturing Crohn’s disease.

Radiology

Radiological imaging is complementary to clinical and endoscopic assessment. It is used in the initial evaluation or diagnosis, preoperative review, to highlight the presence of complications during exacerbations and to evaluate extra-intestinal manifestations. Radiological examination still plays a key role in IBD affecting the small bowel, although endoscopy has generally replaced conventional X-ray examinations of the colon.

Computed tomography (CT scan) and magnetic resonance imagery (MRI) are the best radiological methods for locating and defining fistulae and abscesses in active Crohn’s disease.

Radiolabelled leucocyte scans that utilise autologous leucocytes labelled with ⁹⁹technetium-hexamethylenamine oxime may provide further information of disease site and severity.

Laboratory findings

Although not diagnostic, active disease is suggested in patients with raised inflammatory markers that include erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in addition to a low haemoglobin and raised platelet count. Vitamin B₁₂ may be low in patients with chronic terminal ileal disease. Low red cell folate and serum albumin, magnesium, calcium, zinc and essential fatty acids also indicate chronic inflammation and malabsorption. Anti-Saccharomyces cerevisiae antibodies (ASCA) are more likely to be present in Crohn’s disease. Serology can be used to exclude infection as a cause of diarrhoea.

Malabsorption, indicated by low serum trace elements, for example, magnesium and zinc, is not seen in ulcerative colitis. Low albumin may indicate relapse in active disease. Patients with sclerosing cholangitis often present with altered liver function tests.

Stool tests

Red and white blood cells can be seen on microscopic examination of fresh stools. Microscopic identification of infective cells such as amoeba may also be visualised. C. difficile toxin can be assessed through culture and toxin assay. Stool tests do not diagnose IBD but contribute to excluding alternative diagnoses.

Clinical assessment tools

The Crohn’s Disease Activity Index (CDAI) or the Harvey–Bradshaw Index (HBI) is used in most clinical trials to define remission in Crohn’s disease. However, in clinical practice the CDAI is rarely used as it needs to be measured prospectively and is complex. The HBI is a simple measure of stool frequency, pain and other clinical features that is increasingly used to document selection for and response to biologic therapy. A CDAI of <150 or an HBI ≤3 suggests patient is in remission (NICE, 2010).

The Truelove and Witts criteria is a useful tool in defining the severity of ulcerative colitis (see Table 13.3). A severe attack is defined as more than six bloody stools a day plus one or more of the following: pulse > 90 beats/min, temperature >37.8 °C, haemoglobin <10.5 g/dL or ESR >30 mm/h. In this case, the patient should be admitted to hospital.

Table 13.3 Truelove and Witts criteria for assessing severity of ulcerative colitis (Travis et al., 2008)

Remission in ulcerative colitis is defined as complete resolution of symptoms with a normal bowel pattern (< 3 stools/day), no urgency and no visible bleeding. Mucosal healing is confirmed by endoscopy. Steroid-free remission is the goal of therapy.

Nutritional therapy

Nutritional therapy can be considered as an adjunctive or primary treatment. Although a potential problem for all patients with IBD, patients with Crohn’s disease are at particular risk of becoming malnourished and developing a variety of nutritional deficiencies (Fig. 13.3). It is, therefore, important for patients to receive optimal nutrition and dietary manipulation as needed. Low-fibre diets help to reduce clinical symptoms of intestinal obstruction in Crohn’s disease (Fernandes-Banares et al., 1999). Functional and structural damage to the small bowel can cause malabsorption problems and occasionally patients may require a low-lactose diet. Patients with poor oral intake and loss of appetite often respond to supplemental enteral feeds. Enteral nutrition in the form of an elemental or polymeric diet can be used as primary therapy and is widely employed in paediatrics (Heuschkel and Walker-Smith, 1999).

Patients who have extensive small bowel resection may experience many nutritional deficiencies because of malabsorption. Iron depletion, hypoproteinaemia, deficiencies in water- and fat-soluble vitamins, trace elements and electrolytes may all occur and must be corrected using a suitable replacement regimen.

Where appropriate, and when enteral nutrition is not indicated or adequate, a total parenteral nutrition (TPN) regimen may be prescribed. Some patients receive concurrent enteral and parenteral feeding.

Drug treatment

The main goals of drug treatment are to treat acute attacks promptly and effectively, induce and maintain remission, limit drug toxicity, modify the pattern of disease, avoid and/or manage complications and select patients who will benefit from surgery. Morbidity and mortality can also be reduced by the prompt use of effective and appropriate drug therapy. The choice of drug and route of administration depends on the site, extent and severity of the disease together with the individual’s treatment history. Drug therapy is often required for many years and patient preference, acceptability and possible side effects not only affect choice but will impact on medication adherence. There is a need for therapeutic strategy and consistency in the management of patients with IBD.

Corticosteroids, aminosalicylates and immunosuppressive agents (immunomodulators) such as azathioprine are the mainstays of treatment. Immunomodulators are not licensed for use in IBD but are routinely used.

Modern advances in treatment, such as the use of humanised monoclonal antibody preparations and other biologic agents which modify the affected biochemical inflammatory pathways, now have a significant role in treatment of the disease. These are likely to be the main area of future development.

Other drugs such as antibiotics, for example, metronidazole, are helpful in some cases, while colestyramine, thalidomide, sodium cromoglicate, bismuth and arsenical salts, nicotine, lidocaine, sucralfate, new steroid entities, cytoprotective agents, aloe vera, probiotics and fish oils are rarely used. However, for some patients they provide alternative or supplemental therapy.

The choice of drug treatment is dependent on whether it is prescribed to induce remission or as maintenance therapy. The majority of patients are managed successfully as hospital outpatients or by their primary care doctor. Only severe extensive or fulminant disease requires hospitalisation and the use of parenteral therapy and/or surgical intervention. Oral medication can be given to most patients for maintenance of moderate disease.

The route of administration is a particularly important factor in IBD. In contrast to most other conditions, minimal systemic absorption and maximal intestinal wall drug levels are required with oral therapy. Several delivery strategies have been used to achieve this including the chemical modification of drug molecules, delayed and controlled-release formulations and the use of bioadhesive particles.

Disease confined to the anus, rectum or left side of the colon is more appropriately treated with rectally administered topical preparations where the drug is applied directly to the site of inflammation (Table 13.4).

Table 13.4 Comparison of commercially available preparations for rectal administration in inflammatory bowel disease

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