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Inflammatory Bowel Disease

The topics that I’d like to cover include the definitions, the etiology and the epidemiology of inflammatory bowel disease. The pathology, the complications, the presentation, and therapy and prognosis will also be discussed.

There is a spectrum of presentations in inflammatory bowel diseases. The major ones are ulcerative colitis and Crohn’s disease. There are minor ones, such as microscopic colitis. Ulcerative colitis is a mucosal disease and effects the colon only, whereas Crohn’s disease is a transmural disease, with inflammation through all the layers of the bowel, associated with ileitis, ileocolitis, and colitis, inflammatory bowel disease, ulcerative colitis, ulcertive colitis, Crohn's disease, Crohns disease, crohn disease, cron's disease, crons disease

The etiology of inflammatory bowel disease really is unknown, but there are several lines of evidence involving disordered immune regulation, stimulation of the bowel by intestinal luminal antigens, particularly bacterial, altered permeability of the intestinal epithelium and the generation of soluble mediators of inflammation. This area has been the greatest area of expansion in our knowledge of recent times. The cytokines are deeply involved in the pathogenesis of inflammatory bowel disease and our knowledge of cytokines has exploded in the last few years. There are several pairs of cytokines, pro-inflammatory and anti-inflammatory pairs. So IO-1 is the pro-inflammatory cytokine of the two. IO-1 receptor antagonist is anti-inflammatory and so you can match them across here with TNF IL8 and TGF beta. Our knowledge of these has 

Inflammatory bowel disease seems to be a western disease. Highest incidence areas cover North America, Europe, Australia and South Africa. These are fairly common diseases. Crohn’s disease is less common than ulcerative colitis. The ratio is about 3:10 to 8:10. Incidences of 5:8 per 100,000 population per year for UC, 5:6 for Crohn’s,

Heredity in inflammatory bowel disease is a great concern for patients and their families and indeed there is a 10% to 25% occurrence of inflammatory bowel disease in relatives of those affected. Interesting study from Bayliss in

Pathology is something we all waded through in medical school but it’s terribly important for the understanding of these diseases, in fact I would say it’s the key to understanding what’s going on in your IBD patients. Ulcerative colitis, if you look at it macroscopically, it’s a continuous disease starting at the rectum. If it’s mild you might only

Pseudopolyps are a non-malignant phenomenon. They are an inflammatory phenomenon. You can see here in

Crohn’s disease is very different, as I said. It can occur anywhere from the mouth to the anus. But the commonest sites of involvement particularly are the ileocolonic region with almost half of patients having involvement here. A third will have small bowel alone and about a fifth will have colonic disease alone. Perineal complications are typical of Crohn’s disease and characteristic and occur in about a third of patients. Here we can see a perianal fistulae and abscess formation. This is a cross-section of the rectum and the anus, external skin tag here, with a sinus and fistula tract formation and an abscess. It’s important to remember that Crohn’s disease is transmural and this explains a lot of its complications. Here we have the mucosa, a cross-section all the way through to the serosa and see that there is deep ulceration but in a focal distribution. There’s a sinus tract in here and there’s a fistulous tract all the way to the serosa as well as inflammatory cells within the layers of the bowel. This is the endoscopic appearance of Crohn’s disease. Typically you can see aphthous ulcers which are very discreet, small, 1 mm or 2 mm ulceration’s which actually occur over a lymphoid aggregates. Then you get larger ulceration’s which are typically stellate or longitudinal so there’s deep ulceration here with intervening normal mucosa around the ulcer. You may also get pseudo-polyps in Crohn’s disease due to the exuberant inflammatory response.

Obstruction, because of the transmural nature of Crohn’s disease, is common. This is terminal ileitis. Here’s the cecum and the appendix. You can see intense narrowing here with dilatation in between due to inflammation and possibly fibrosis in the bowel wall. This is fistula formation. This is aortoenteric fistula in Crohn’s disease where a tract has burrowed out from the mucosa to the serosa, attached itself to another loop of bowel and you have a short

So to summarize features of UC versus Crohn’s, very important features are the site. Ulcerative colitis is colonic, Crohn’s involves the small bowel and the colon, although it may be exclusively colonic. The pattern here is continuous from the rectum, whereas in Crohn’s there will be skipped areas. The inflammation is mucosal in ulcerative colitis and continuous, whereas it is transmural and focal in Crohn’s disease. Perianal disease is uncommon in UC, common in Crohn’s. Fistulae do not occur in UC, they do in Crohn’s. Strictures are relatively uncommon in UC and quite common in Crohn’s.

If you look at the acute complications of inflammatory bowel disease, exsanguinating hemorrhage is certainly a risk. Toxicity and perforation, obstruction -whether it’s due to benign strictures or malignant complications. Abscess formation which may be abdominal, perianal or perirectal. Here’s an illustration of toxicity in the colon. On the left -

There are complications of inflammatory bowel disease related to chronic inflammation, and the systemic complications are glomerulonephritis and amyloidosis related to the elevated inflammatory proteins and immune complexes. This is relatively uncommon now that we have better treatments. Local complications are still common.

Systemic complications of inflammatory bowel disease can be related to the inflammatory activities so that if you control the inflammatory bowel disease, you control these manifestations; including aphthous stomatitis, episcleritis and uveitis, arthritis which is typically monoarticular and peripheral and is not destructive. The vascular complications, such as thrombophlebitis, erythema nodosum and pyoderma gangrenosum, the chronic skin lesions. There are systemic complications that do not resolve with treatment of the underlying inflammatory bowel disease, and important among these is the central or axial arthritis which is related HLA B-27 positivity. Here you can see an extensive ankylosis of the spine and the surgical clips from the colectomy, which did not help the spine. This is a lateral view of the same thing.

Similarly, liver and bile duct lesions tend to follow their own course and can include anything from fatty change to chronic active hepatitis, sclerosing cholangitis and cholangiocarcinoma. These are cholangiograms from patients with

There are complications related to the small bowel pathology, and clearly if you have Crohn’s disease you have the potential to malabsorb. And once malabsorption becomes chronic, you’re at risk for gallstones and also renal stones

Colorectal cancer is one of the most feared complications of inflammatory bowel disease and this slide illustrates the risk of colorectal cancer in ulcerative colitis. This is cumulative incidence by decade of disease. This is incidence by

In Crohn’s disease there’s in increased risk of gastrointestinal cancers, but the incidence of this is somewhat unclear and debated. Two-thirds of the malignancies will occur in the diseased bowel and one-third will occur in the

So how does inflammatory bowel disease present to you, the practicing physician? Importantly, one of the commonest presentations is with proctocolitis and unfortunately this is a lesion that can have many different causes, including ulcerative colitis, Crohn’s disease, radiation, ischemia, infections, antibiotics and other rarer causes. So

We move on now to the therapy of inflammatory bowel disease, and clearly the major categories are: medical, surgical, supportive - such as nutritional and stoma - and social and psychological support, which is very important.

If you look at the 5- ASA drugs, sulfasalazine is the mainstay that has been with us for many years, and the cheapest. It’s an oral formulation. Olsalazine is used less now because of its side-effects. It’s also an oral formulation. Mesalamine is really the drug of choice now for remission reduction for mild and moderate disease and it comes in oral and enema form, and para-aminosalicylic acid is available overseas but

This is an illustration of the structure of sulfasalazine just to remind you that really the part that works is the aminosalicylate and the part that gives the side-effects is the sulfapyridine, and unfortunately you are stuck with the two of them when you use this drug. Five-ASA drugs, as I’ve mentioned, are used for maintenance of remission in

This is an illustration of the effect of 5-ASA in active ulcerative colitis. Here you can see a nice dose response curve where the 4.8 grams a day causes improvement in 50% and remission in 25%, and so on down to placebo, where you have very low rates of improvement. It’s important to remember that this is a lot of pills for the patient to take, but it may well be worthwhile. Sulfasalazine is still very widely used because of its low cost and has major side-effects, including allergic reactions all the way through to the severity of Stevens-Johnson; hemolysis, agranulocytosis and severe organ toxicities are all a concern. The common side-effects, however, are the patients main concern. And these are nausea and dyspepsia, anorexia, headaches which may be of a migraine-type, mild hemolysis, folate deficiency and importantly reversible male infertility. Now we have the other option of mesalamine.

Systemic glucocorticoids are used in IBD. These include prednisone and prednisolone. All are IV. They induce remission in acute IBD, they reverse life-threatening colitis. They are not helpful for maintenance of remission and

The main drug that’s been studied is budesonide, other than the traditional enemas for proctocolitis and distal colitis. All of these drugs rely on low bioavailability and they are all in enema form. Budesonide is an oral agent. It’s topically active due to liver metabolism. It induces remission in active Crohn’s disease and ulcerative colitis and will be most welcome when it gets on the market.

If you want to move on to stronger immunosuppression, the most commonly used drug is mercaptopurine or azathioprine as precursor. Here you can see the effects of azathioprine in active Crohn’s disease, in achieving steroid typhi, inhaling fistulae and in overall clinical improvement as 

Cytokine therapies are new are certainly not available on the market yet, but the most exciting development in the last few years in IBD, and this is the clinical application of all that knowledge we gained on cytokines in research models. The ones being used are monoclonal antibodies to TNF alpha, recombinant IO-10, recombinant IO-11 and anti-sense molecule to ICAM-1. The recent study in the New England Journal showed a dramatic response of Crohn’s disease to a chimerical monoclonal antibody called CA-2 to __ necrosis factor alpha. This is looking at

Antibiotics, as I said, can be useful and the classic one used in IBD is metronidazole. The indications are mostly in Crohn’s disease, for perianal disease, mild to moderate colitis, ileocolitis and possibly ileitis. It does have toxicities, including nausea and orexia, diarrhea, furry tongue, monilial infections, puerperal neuropathy is the one I would point

Nutrition in IBD is very important. Obviously if something upsets your stomach, don’t eat it. It’s hard to convince

Smoking is a very important issue in inflammatory bowel disease as more and more evidence comes to light.

Symptomatic treatment is very important in inflammatory bowel disease. We do use antidiarrheals as long as we are

The indications for surgery are very important. In ulcerative colitis this is a curative surgery but still it’s reserved for severe cases: exsanguinating hemorrhage, toxicity and perforation, suspected cancer - which goes along with high grade dysplasia, growth retardation, systemic complications and intractability are all important indications. Surgical options, as you probably know, include conventional ileostomy, continent ileostomy or Koch pouch and the