Today we are presenting a lecture on Crohn’s disease. The learning objectives of today is to first understand the epidemiology and pathophysiology of Crohn’s disease, and to develop the ability to recognize the manifestations of Crohn’s disease clinically, learn about how to diagnose Crohn’s, be able to identify the histological features for Crohn’s. At the end of the presentation, the student should have a general idea of the different methods to classify the disease and its severity, and at the same time, understand the possible complications of the disease. The student should have a brief understanding of the possible treatment options available. Epidemiology. Within Europe and North America, there seems to be a north to south gradient in the frequency of Inflammatory Bowel Disease, or IBD. The highest incidence is observed in temperate climates and more industrialized parts of the world, such as Western Europe and North America. In most Western European countries, the incidence has stabilized, averaging 7 per 100,000 persons, while the incidence in Asian countries seem to be significantly lower. The age of onset is bimodally distributed with the first peak being at 15 to 30 years old, while the second peak is usually women at around 60 to 70 years old. The frequencies of IBD is similar in both genders. Frequency, however, in the pediatric population is reversed, where there’s a higher incidence in boys. Pathophysiology of Crohn’s disease. Crohn’s disease is a lifelong disease observed primarily in the developed countries. It arises from a complex interaction between genetic and disturbances of physiologic environment and pathways, as well as environmental factors. In the genetics of Crohn’s disease, a mutation in the NOD2 or CARD15 gene, which is produced by the Paneth cells in the base of the intestinal crypts, causes a defective sensing intracellular bacteria resulting in reduced production of defensins. A mutation in the ATG16L1 autophagy gene also causes a decrease in exocytosis of secretory granules in Paneth cells, thereby decreasing crypt concentrations of defensins, lysozymes, phospholipase A2. A major component in the pathophysiology of Crohn’s disease consists of host’s immune response dysregulation. Mucosal defense mechanisms include mucus-coated epithelium with tight junctions, IgA secretion, and defensins. There is a dysregulated proinflammatory response and overly aggressive acquired T cell immune response to commensal gut bacteria that develop in genetically susceptible hosts. Defense mechanisms depressed, leading to uncontrolled microbial proliferation and K kappa B dependent genes stimulated to produce proinflammatory cytokines, such as TNF-alpha, interleukin 1 and 6, chemokine, and interleukin-8. Cytokine and chemokine production attract T cell infiltration, mainly T helper 1 cells amplifying inflammatory response. Environmental factors are known to have an effect on Crohn’s disease. These include smoking, which has been shown to double this risk of Crohn’s. Crohn’s may also improve when changed to a liquid diet. And fatty foods exacerbate Crohn’s. Bacterial infections by E. coli, mycobacterium paratuberculosis, and measles virus. And drugs, such as oral contraceptive pills, NSAIDs, has been shown to affect Crohn’s. The clinical presentation of Crohn’s disease. The symptoms of Crohn’s disease are heterogeneous and non-specific, but more commonly includes diarrhea for more than six weeks. Weight loss and abdominal pain is also seen in about 60% to 70% of the population suffering from Crohn’s. While blood or mucus in the stools can be seen in up to 40% to 50% of the patients. Abnormalities of the musculoskeletal system are the most common manifestations of Crohn’s. Because Crohn’s is such a heterogeneous disease, it’s a major challenge in the field of clinical investigation to determine and classify the disease into distinct subsets of patients. Therefore, in 2005, a new revision of the Vienna Classification Scheme in Montreal was proposed to allow for a more accurate disease characterization. The Montreal classification used parameters such as age at diagnosis, location, and behavior to characterize the disease so that the appropriate treatment can be optimized. It’s important for practicing clinicians in clinical decision making, such as when to start immunomodulators. Differential diagnosis for Crohn’s disease. There are conditions that can mimic Crohn’s colitis. And they can be divided into infective and non-infective differentials. I’d like to also point out that tuberculosis infection would be one of the top differentials in Singapore. In tuberculosis infection of the colon, granulomas can also be present. And it can be difficult to differentiate between the two. The diagnosis of Crohn’s disease. Because Crohn’s disease comprises of a variety of complex phenotypes in terms of age, disease location, and behavior, therefore, a combination of evaluation methods is used. The diagnosis of Crohn’s can be broadly classified into macroscopically or microscopically. Macroscopic investigations include clinical endoscopic and radiological investigations. Under clinical evaluation, one should take a full history, including asking about onset of symptoms, recent travel, food intolerances, medication, including antibiotics and NSAID, and history of appendectomy. Also ask about proven risk factors such as smoking, family history, and recent infectious gastroenteritis, and also nocturnal symptoms, other extraintestinal manifestations involving the mouth, skin, eye, or joints. Episodes of perianal abscess or anal fissure is appropriate as well. A general physical examination should be performed and also looking out for abdominal tenderness or distention, palpable masses. Perineal or oral inspection, and rectal digital examination should be performed. Measurement of body weight and calculation of body mass index are recommended. Endoscopic features, looking out for discontinuous involvement or skip lesions, anal lesions, cobblestoning, and strictures. Multiple biopsies, at least two, from five sites around the colon, including rectum and ileum, should be obtained for proper diagnosis. Radiological investigations, such as CT or MRI, are of similar diagnostic accuracy for small intestine inflammatory lesions. MR and CT enterography or enteroclysis is an imaging technique with the highest diagnostic accuracy for the detection of intestinal involvement and penetrating lesions in Crohn’s used to establish disease extension and activity based on wall thickness and increased IV contrast enhancement. Other imaging techniques include abdominal ultrasound, leukocyte scintigraphy, small bowel capsule endoscopy, and double-balloon enteroscopy. Biochemical investigations, looking out for anemia, thrombocytosis, and hypoalbuminemia. There might also be electrolyte abnormalities. One should also do liver function tests, looking out for raised alkaline phosphatase and gamma glutamyl transferase levels. Raised CRP of protein or erythrocite sedimentation rate are some of the common changes in the blood work of patients with Crohn’s. Histological features for diagnosis of Crohn’s. Microscopically, the features include transmural inflammation with multiple lymphoid aggregates, chronic inflammation areas with increased lamina propria plasma cells and lymphocytes, submucosal thickening, neuromuscular hyperplasia of the submucosa, crypt irregularity with crypt loss, abscess, architectural distortion. Skip lesions comprising of focal patch erosions or ulcers, vertical fissures, and fistulas. Sarcoid granuloma, including in lymph nodes that are non-necrotizing well-circumscribed groups of epithelioid histocytes, with or without accompanying giant cells of the Langerhan type, and fissures. Complications of Crohn’s disease. Since Crohn’s is a systemic disease and can cause many different kinds of complications with varying severities, not everyone with Crohn’s disease will experience these complications. However, early recognition and prompt treatment is key. The intestinal complications tend to occur when the intestinal inflammation is severe, widespread, chronic, and transmural. They are anal and perianal complications. Undernutrition, short bowel syndrome, increased risk of colorectal carcinoma, intra-abdominal abscess. Extraintestinal complications are illustrated in the following picture. And they can be divided into either occurring during the active phase, whereby you have complications such as erythema nodosum, pyoderma gangrenosum, episcleritis and uveitis, and arthropathy. Or unrelated to inflammatory bowel disease activities, such as sclerosing cholangitis, ankylosing spondylitis, and osteoporosis. In order to describe the different classification of disease severity for research purposes, an arbitrary numerical figure known as the Crohn’s Disease Activity Index, or CDAI, is used. Different treatments are recommended at different grades of severity. In the treatment of Crohn’s disease, there are many modalities of treatments available. However, the management plan should take into account the activity site and behavior of the disease, which should always been discussed with the patient. The appropriate choice of medication is often a balance between the drug potency and potential side effects, previous response to treatment for refractory disease, and also the presence of extraintestinal manifestation or complications. Different drug preparations can be released at different sites and can have local focus activity. Therefore, the treatment administered to the patient is always best tailored to the individual patient’s severity and pattern of disease. The details of different medications for different severity and involvement is out of the scope of this presentation. One can see that it is the multi-disciplinary approach, involving dietary changes, nutritional and pharmaceutical therapies. It’s also important to note that surgery does play an important part in the treatment of Crohn’s. However, surgery is often the treatment of last resort as it carries implicit risk and entails higher risk of septic complications. In summary, Crohn’s is a lifelong disease. But early intervention and intensive therapy appears to improve healing and sustain remission of the disease. It is therefore important to clinically recognize the nonspecific symptoms of Crohn’s and utilize the appropriate investigative modalities to secure a diagnosis. It is also important that the disease is appropriately classified in terms of behavior and severity, allowing optimal therapy to be administered. Management of Crohn’s requires a multi-disciplinary approach involving medical, therapy, surgical and non-pharmacological interventions, as well as social support. It’s therefore critical that the management of Crohn’s is individually tailored and closely discussed with the patient. Here are some key references.