Crohn Disease

00:02 Welcome. In this talk, we're going to discuss one of the forms of inflammatory bowel disease, Crohn's Disease.

00:08 Crohn's Disease, and you'll see it abbreviated CD on the slides, is inflammatory bowel disease than can affect any portion of the GI tract.

00:18 It's also called regional enteritis but anything from mouth to anus can be affected by Crohn's Disease.

00:26 The inflammation in Crohn's Disease or regional enteritis is classically a granulomatous inflammation, suggesting that there are certain types of pro-inflammatory mediators driving a type 1, a Th1 helper phenotype.

00:41 There is transmural inflammation and importantly, there's the formation of fistulous tracts connecting bowel to bowel, bowel to bladder, bowel to skin.

00:51 And those distinguish this Crohn's Disease from Ulcerative Colitis.

00:57 The epidemiology. So, the incidence is not high. But if you have it, you know you have it.

01:06 About three to 20 per 100,000 adults per year.

01:09 There is a bimodal distribution with late teenage years and early adult years, and a smaller peak later on in life.

01:17 The frequency between men and women is comparable.

01:20 Risk factors include smoking, although, smoking is associated with a lot of other things and it's just a epidemiologic association.

01:29 We don't truly understand why. If there's a family history of inflammatory bowel disease, that does increase your risk.

01:36 And as we'll see, there's a very strong genetic component.

01:39 In fact, the twin concordance rate, identical twins, if one twin has it greater than 50% of the time, the other twin will have it as well.

01:49 And interestingly, 15% of patients who have Crohn's Disease, will have an affected first-degree relative, brother, sister, mother, father.

02:00 The genetics show an association epidemiologically with HLA-B27 and also with pleomorphism in the NOD2 genes that's involved in immune regulation.

02:13 Pathophysiology. It's really fairly straightforward.

02:19 Although, the reasons that any particular individual has dysregulation of immune response are not completely understood.

02:26 But once the immune response is dysregulated, we understand it pretty well.

02:31 We're looking at normal epithelium here shown in the small bowel because we have a Paneth cell that is present.

02:38 The normal epithelium is a tall columnar epithelium. It makes a - it has a villous layer and microvilli on the surface.

02:46 It makes mucus. There are tight junctions that keep the luminal contents within the lumen and the extra luminal contents like blood and connective tissue out of the lumen.

02:57 Within the extraluminal space within the laminar propria, there is a normal conversation going on between macrophages and dendritic cells that are sampling in many respects what is in the luminal contents.

03:13 So there will be bacteria there.

03:15 Dendritic cells and macrophages being antigen presenting cells are sampling that and they are in most cases turning on the formation of regulatory T-cells, not pro-inflammatory but T-cells that are going to say, "Oh, those contents - no, those bacteria in the GI tract, they're cool.

03:34 Leave them alone." And we will get expansion of the regulatory T-cell population.

03:38 So, that's how we have this commensal relationship with most of the bugs, the microbiota that live within our GI tract.

03:46 That's the normal situation. In patients who have Crohn's Disease, there will be a variety of mutations and the NOD2 mutation which is going to be involved in innate immune responses is a classic one.

04:02 But in all cases, what we have is a primary dysregulation of a variety of things at the level of the epithelium or at the level of the inflammatory response. So, you may have dysregulated tight junctions.

04:15 You may have dysregulated mucin production. You may have dysregulated paneth cells.

04:22 And in all those settings, we may have an ability for the microbiota to transverse the epithelium.

04:31 In association with that, we also have a defective regulation of tight junctions and we have changes potentially in the microbiota.

04:31 Those come across and are processed and presented.

04:31 Those come across and are processed and presented.

04:36 And in individuals who are going to be prone to having inflammatory bowel disease, we will regulate or upregulate, induce the production of pro-inflammatory T-cells.

04:47 Predominantly in Crohn's disease, Th1, T helper 1 variety.

04:52 That expansion then gets us many more of the Th1 helper T-cells, not regulatory T-cells but pro-inflammatory T-cells that will drive the inflammatory process. The clinical presentation.

05:05 The GI manifestations are related to malabsorption and inflammation.

05:12 So, there will be chronic, intermittent diarrhea.

05:14 It's usually non-bloody but it can be bloody depending on the degree of invasion and the degree of injury to the epithelium.

05:23 There's crampy abdominal pain because of the malabsorption.

05:26 What we're getting is nutrition, nutrients not being appropriately absorbed, and then, bacteria fermenting those.

05:33 But you can also have because of inflammation, the bowel spasming, smooth muscle contracting.

05:39 There may be, depending if you have disease that involves the upper GI tract, odynophagia, pain on swallowing or abnormal difficult swallowing, dysphagia.

05:49 There may be flatulence and bloating associated with fermentation of poorly absorbed nutrients.

05:55 There may be fecal incontinence because of spasming of the small bowel, particularly, within the rectum and anus. You may evacuate stool contents inappropriately.

06:06 And depending on the degree of involvement and where the involvement is in the GI Tract, you may have signs of malabsorption.

06:12 You will also, because again, this is a pro-inflammatory process, tend to have a low-grade fever.

06:19 You may have other signs related to the elaboration of pro-inflammatory mediators like TNF, Tumor Necrosis Factor and interleukin-1, you may lose your appetite. With malabsorption, you're going to have weight loss.

06:32 You may have anemia, again, because of malabsorption of important nutrients for normal red cell and red cell development.

06:40 In children who have this, they may have failure to thrive or growth retardation.

06:46 The extraintestinal manifestations are multiple.

06:50 And they may be due to a general pro-inflammatory environment within these patients, maybe secondary to the malabsorption or maybe due to local mucosal effects in other areas of the body.

07:05 So, aphthous ulcers, painless oral ulcers may be part of this.

07:09 You may get gallstones because you don't have normal bile acid reabsorption from the GI tract if that's where it's affected.

07:16 Kidney stones will happen because there's decreased fat absorption and it gives us increased excretion of calcium oxalate within the blood stream and the kidney.

07:27 And pyoderma gangrenous which is a painful papule and pustules in the skin.

07:32 Other extraintestinal manifestations, erythema nodosum, a pro-inflammatory erythematous nodule typically on skin, eye inflammation, you may have arthritis and ankylosing spondylitis and osteoporosis will also occur.

07:50 The later because you have malabsorption and not absorbing calcium appropriately.

07:55 Making the diagnosis in the primary setting. Part of this involves seeing how serious the malabsorption is.

08:03 So, we'll do a CBC. We'll be looking for elements of anemia and what kind of anemia, microcytic or macrocytic.

08:09 We may be looking for leukocytosis, we may be looking for thrombocytosis.

08:13 All those are pro-inflammatory markers. We'll look for electrolyte imbalances.

08:18 We will specifically assess for iron or vitamin B, B12 or folate deficiency.

08:24 An elevated erythrocyte sedimentation rate or elevated C-reactive protein are important kind of systemic pro-inflammatory markers and will be elevated in Crohn's Disease.

08:35 We want to exclude other causes. So, we're going to exclude infection. We're going to exclude Clostridioides difficile toxin.

08:43 We will look for the presence of blood. Blood can be present in inflammatory bowel disease or may not be present.

08:53 But if we have a lot of blood, that's going to suggest another cause perhaps.

08:57 CT is going to be in some respects, somewhat helpful if you see focal areas of bowel thickening or induration.

09:05 But ultimately, it's going to come down to colonoscopy and biopsy. And that's where the pathologist comes in.

09:12 This image is what we would see classically on endoscopy.

09:15 We have a lesion of focal ulceration and then, when we biopsy that zone, we see markedly increased inflammation with non-caseating granulomas.

09:26 Now, importantly, just as kind of a take home message, you won't always see the non-caseating granulomas in a Crohn's biopsy.

09:34 In fact, only about 50% of cases will have that.

09:38 However, the presence of a non-caseating granuloma is very highly supportive of that diagnosis and not for example, ulcerative colitis.

09:49 On imaging, so, we have opacified all of the bowel but with a barium ingestion.

09:59 That can demonstrate fistulous tracts. It can demonstrate focal areas of bowel wall thickening due to inflammation.

10:08 The management. So, we need to make sure that we cover out bases in terms of metabolic derangements.

10:17 If there is a vitamin B12 or a vitamin D insufficiency due to malabsorption, we need to make sure that we cover that.

10:26 We need to give anti-diarrheal patients so that the patient, the poor patient, isn't sitting all day on a toilet.

10:33 We may do targeted medical therapy.

10:35 So, in some cases, antibiotics are quite helpful by changing the bacterial milieu within the lumen.

10:44 Anti-inflammatory agents such as corticosteroids or immunomodulators such as azathioprine or mesalamine.

10:51 Or specifically, anti-cytokine therapies, anti-tumor necrosis factor therapies like infliximab or adalimumab.

10:59 And then, if we have fistulous tracts, that may require that there be surgical intervention.

11:07 So, we may have to take out portions of the intestine.

11:09 There is with chronic inflammation in any epithelium that's regenerating, a risk for cancer and we will have to constantly monitor in patients who have long-term reactive Crohn's Disease.

11:24 We'll have to monitor them for the development of adenocarcinoma.

11:27 And with that, we've reached the end of Crohn's Disease.