1.4.2 are a very common problem in

1.4.2 Disease classificationThe Montreal classification of CD71 classifies CD according to the age of onset (A) disease location (L) and disease behaviour (B) as described in Table 2.

Montreal classification of Crohn’s diseaseAge at diagnosis (A) Disease location (L)* Disease Behaviour (B)A1 16 years or younger L1 Terminal ileum B1 nonstricturing nonpenetratingA2 17-39 years L2 Colon B2 stricturingA3 over40 years L3 Ilecolon B3 penetrating L4 Upper GI Table 2: Summary of Montreal CD classification71 according to the (A) age at diagnosis, (L) disease location, (B) disease behaviour. *A perianal disease modifier may be added in the presence of perianal fistulas. This will not be discussed any further in this thesis.1.

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4.3 SymptomsCD can present with a variety of symptoms but nutritional abnormalities are a very common problem in this disease. Up to 85% of IBD patients suffer from nutritional deficiencies with protein-calorie malnutrition common when in an active phase of the disease72 Micronutrient deficiencies are also a recognisable issue in remission73. In CD, up to 75% of hospitalized patients are malnourished74. Increased intestinal losses, anorexia and inflammation appear to contribute to malnutrition in CD74. Most patients’ symptoms in CD occur postprandially after feeding rather than after a prolonged fast.

CD patients suffer from acute or chronic diarrhoea, abdominal pain, bloating, and weight loss60. Specific symptoms of CD may vary in between patients but this tends to depend broadly on the predominant disease location. Patients with a predominant colonic distribution of the disease tend to present mainly with chronic diarrhoea and rectal bleeding, while patients with small bowel disease can present with a change in bowel habit, abdominal pain and predominant obstructive symptoms.

These symptoms have a significant influence on patients’ lives. In a survey study of 5636 patients 75 75.6% of the patients reported that symptoms affected their ability to enjoy leisure activities like travel, dining and sports and in 68.9% the symptoms affected their ability to perform at workplace75.1.4.

4 DiagnosisA number of investigations may be needed to diagnose CD as a significant number of related symptoms can be non-specific and shared with other common conditions like irritable bowel syndrome, coeliac disease, intra-abdominal malignancy and ulcerative colitis. There is no single gold standard test to diagnose CD. The diagnosis is confirmed by clinical evaluation and a combination of haematological, biochemical, endoscopic, histological and imaging-based investigations61. Initial mandatory laboratory tests include full blood count, urea and electrolytes, liver function tests, and C-reactive protein (CRP)60.

The most common findings in the laboratory tests in patients with CD are anaemia, a high white cell count, thrombocytosis, and raised inflammatory markers60. Faecal calprotectin (fC), a granulocyte protein shed into faeces by the inflamed bowel, has been used in recent years as a marker of disease activity. Meta-analyses estimate it has 80-87% sensitivity (Sn) and 68-82% specificity (Sp) for clinical76 and endoscopic77 CD activity, and 78% Sn and 73% Sp to predict relapse78. Recent data has indicated that fC might be less sensitive as a marker of small bowel disease79.

To this effect, the correlation co-efficient of faecal calprotectin with endoscopic and histological parameters of disease activity is reduced in small bowel disease when compared to large bowel disease80.Different imaging modalities are available to diagnose and evaluate the extent and the severity of the disease and to investigate the suspected complications. A plain abdominal x-ray is sometimes necessary for the initial assessment of patients with CD in order to exclude obstructive complications61. Endoscopic examination through a colonoscopy is the gold standard investigation as it provides the opportunity of a close inspection of the intestinal mucosa and the ability to obtain histological samples for microscopic assessment of the disease. Intuitively, colonoscopy is highly useful for colonic disease but has a limited role in the diagnosis and follow-up of small bowel disease especially if this has a proximal or mid small bowel location as it cannot be reached60.

A simple endoscopic score system for CD (SES-CD) is used in clinics based on endoscopic variables81. Small bowel capsule endoscopy (SBCE) has a high sensitivity for detecting small bowel disease but the effectiveness of this modality is limited by inter-observer variability and limited availability within medical institutions. Moreover, it is impossible for SBCE to assess the extra luminal disease extent82. Ultrasound has also been used in the diagnosis of CD. It has the ability to visualise the changes in the bowel wall without the use of ionising radiation. The contribution of newly developed techniques in intestinal ultrasound has been shown in CD.

Contrast-enhanced ultrasonography (CEUS) demonstrated a high sensitivity and specificity in predicting disease activity in CD83 and in evaluating postoperative recurrence in CD84. Another interesting method is the ultrasound elastrography. This method evaluates the changes in tissue elasticity and stiffness in pathological conditions85. Recent studies based on this technique suggested that it can be used in evaluating CD86, 87. In addition, a multi-centre clinical trial has been launched recently aimed to compare and evaluate the diagnostic accuracy of MRI and ultrasound in CD88.Recently, MRI and CT have been widely used because of their accuracy in detecting small bowel inflammatory lesions60.

Additionally, both MRI and CT are capable of indicating the disease extension and activity based on the wall thickness and increased intravenous contrast enhancement60. CT is widely available and is less time-consuming than MRI61, however the use of MRI in CD assessment has recently increased for specific reasons. One major disadvantage of CT is the high radiation exposure specially with repeated examinations82.

MRI has better soft tissue contrast and multi-planar capability. Moreover, MRI is superior in detecting CD complications and the lack of radiation exposure, together with improved infrastructure, availability and technology makes it the technique of choice for CD patients61. For these reasons MRI has become a recommended technique especially with the modern hardware and software61. MRI has the ability to detect luminal and extra luminal features of CD89. The degree of wall thickness, bowel wall enhancements and wall oedema are important signs of disease activity which can be assessed using MRI90 (Figure 4). Another important sign of CD is the abnormal alteration in bowel motility which can be examined using MRI91. In addition, MRI has the ability to detect fat wrapping (creeping fat) in CD92 which is one of the disease’s features defined by the unusual changes in the appearance of mesenteric adipose tissue in CD patients93. Figure 4: Example of MRI findings seen in CD94.

MRI image of the entire abdomen illustrating the terminal ileum (arrow) showing wall thickening, comb sign, and edema in the surrounding mesenterial tissue94. Advantages of MRI in assessing CD patientsOne of the most important benefits of MRI is the lack of radiation exposure. This is more critical in CD patients because the disease affects mostly young patients. Also, CD patients often need repeated scanning to assess the disease activity and progress, and also to monitor treatment outcomes, making repeated radiation exposure by CT an unsuitable option in the long term. In addition, patients with CD have background risk of neoplasia95. MRI has instead potential advantages for the assessment of disease activity and patient management89. The role of MRI has expanded and researchers are investigating its use in monitoring and evaluating treatment therapies96, 97.

New and emerging MRI techniques have important advantages in measuring disease activity in CD. A significant decrease in contrast enhancement from active to remission in CD was reported with the use of contrast-enhanced T1-weighted MRI 98. The study also demonstrated a significant decrease in wall thickness from active to remission phase suggesting the importance of MRI in detecting pathological changes98. Additionally, the ability of MRI in detecting fibrosis in CD lesions has been shown from analysing 44 segments of 41 patients 99 .

An adequate distention of the bowel can be achieved artificially through nasoduodenal intubation in MRI enterolysis100 and in MRI enterography. MRI enterolysis showed a similar accuracy to conventional enteroclysis (under fluoroscopic guidance) as a diagnostic method in evaluating CD in patients101. In addition, Frokjaer et al102 showed that MRI is superior to conventional enteroclysis in visualising the entire small bowel pathology with less patient discomfort. Another sign of CD is the high mural signal intensity on T2-weighted fat-saturated images which might indicate the presence of mural oedema and contribute to disease activity90. 1.4.5 ManagementThere is no actual cure for CD. The choice of management of Crohn’s disease depends on the severity, the site and the behaviour of the disease103.

Therapeutic options in the management of the disease include nutritional supplementation, smoking cessation, drug therapy, and surgery in severely active or complicated stricturing and penetrating disease61. Smoking cessation resulted in a 65% reduction in the risk of relapse compared to continued smokers104. The aim of the drug therapy is to reduce the inflammatory burden, attenuate or halt disease progression, control the symptoms and optimise quality of life. A variety of drug therapies have been used such as antibiotics, corticosteroids, aminosalicylates, thiopurines, methotrexate, Vedolizumab, ustekinumab and anti-TNF therapy61. Even with appropriate medications and nutrition, patients may ultimately need surgery to reduce the disease’s symptoms and complications. It has been reported that surgery may be required in up to 75% of CD patients after 10 years of the disease105. Recent data highlights a rate of 35% in the first decade with the risk of a second operative procedure of 25% in the next 5 years106. A very recent data showed an overall decrease in the surgical resection rates in CD107.

1.4.6 Peptide dysregulation in CDIn patients with intestinal inflammation, nutritional deficiency is a very common and important clinical problem108. The causes of malnutrition are multifactorial and biological processes other than structural disease have a key role109. In addition, poor appetite, satiety and reduced food intake contribute to the nutritional imbalance in CD109.

Satiety signals produced by gut peptides play a critical role in CD. Changes in the regulation of GI peptides in inflammatory bowel disease are believed to play a fundamental role in the control of food intake. Intestinal inflammation in CD has been associated with increased GI peptides and these peptides have an effect on GI function. This might suggest a link between the alteration in intestinal physiology and malnutrition in CD. The link between peptides regulations in CD and the aversive symptoms is inadequately understood. Animal modelsThe effect of inflammation on food intake has been studied in a mice model of upper gut infection (Trichinella spiralis). Elevated CCK plasma levels were demonstrated with reduced food intake in the affected mice110.

Food intake was increased after treating the mice with CCK1 receptor antagonist110. This indicates that the intestinal inflammation and the increase in CCK may be linked to the reduced food intake. Human models Historical data in eight patients with severe malabsorption showed increase in various gut hormones compared to 12 controls111.

In another study, patients with digestive disorders showed elevated plasma levels of PYY112. In a study done on patients suffering from giardiasis, a significant increase in their postprandial CCK levels was reported compared to healthy controls. Following treatment with metronidazole, plasma CCK levels were normalised and patient symptoms like nausea bloating and anorexia were abolished113.

This suggests a link between intestinal inflammation and the increase in GI peptides and its potential reversibility. CD dataFew studies have considered the EEC peptides in CD and their role is poorly understood. In an early study, ileum specimens were taken from 10 patients with CD.

They demonstrated a significant increase in the EEC population in the ileum measured using immunostaining114. Furthermore, at the tissue level, a significant increase in EEC peptide expression was seen in the terminal ileum of CD patients115. GLP-1 and chromogranin A (CgA) cells in the terminal ileum were increased by 2.5 fold in CD patients while PYY cells were unchanged115. In the same study, mRNA expression of the gut peptides was examined and the results showed a significant increase in the gene expression of CgA and GLP-1 peptides but not PYY115. In a study using breath test, gastric emptying and gut peptides were investigated in 13 CD patients and 13 healthy controls116. A 50% delayed gastric emptying (measured by T1/2) was noted with elevated postprandial levels of gut hormones like CCK, PYY and GLP-1116. In another CD patients study, the link between EEC peptides and appetite related symptoms was investigated in a cohort of 17 patients and 13 healthy controls.

An increase in fasting and postprandial plasma PYY levels was seen and it was associated with symptoms like nausea and bloating109. After treatment, plasma PYY levels were normalised thus suggesting a link between EEC peptides and disease activity109. Recently, Keller et al evaluated gastric emptying in 20 healthy controls and 13 CD patients during active disease and following treatment.

Delayed gastric emptying and elevated levels of GLP-1 were noted in CD patients compared to controls117. After 3-4 months of treatment, gastric emptying was accelerated and the peptides levels were significantly decreased117. Although there is little research aimed at investigating the link between patient symptoms and altered EEC secretions in small bowel CD, symptoms are believed to result from changes in peptide regulation118.


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