UC and CD?
2. ULCERATIVE COLITIS AND CROHN’S DISEASE
Ulcerative colitis is a diffuse mucosal inflammation limited to the colon; it almost always affects the rectum, and it may extend proximally in a symmetrical, uninterrupted pattern to involve all or part of the large intestine. Crohn’s disease, by contrast, is a patchy transmural inflammation that may involve any part of the gastrointestinal tract from mouth to anus.
characteristics of UC?
4. CHARACTERISTIC FEATURES OF ULCERATIVE COLITIS
The typical pattern of ulcerative colitis is chronic inflammation limited to the mucosa of the colon, occurring in a continuous symmetrical distribution from the rectum proximally to all or part of the rest of the large bowel.
anatomy of UC?
5. ANATOMIC EXTENT OF ULCERATIVE COLITIS
At least half of all cases of ulcerative colitis in the community at large are limited to the rectum (proctitis) or rectosigmoid (proctosigmoiditis). About 10% of all cases may present initially involving the entire large bowel (universal or pancolitis). Intermediate distributions are usually characterized as left-sided (involving the descending colon up to but not beyond the splenic flexure) or extensive (extending proximal to the splenic flexure). It is estimated that 10-30% of cases that are initially confined to the rectosigmoid or descending colon may ultimately spread further proximally with a worsening clinical course.
• Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis: a long-term follow-up of 1116 patients. Dig Dis Sci 1993;38:1137-46.
7. ENDOSCOPIC SPECTRUM OF SEVERITY
In the normal colon, the mucosa is a shiny, pale pink and retains a delicate, reticulated vascular pattern. In mild ulcerative colitis, the mucosa becomes duller and redder, often with a “granular” or fine sandpaper-like texture, and the vascular pattern is obscured. In moderate cases, gross pitting of the mucosa is seen and the lining may crumble away and bleed at the lightest touch (friability). The most severe instances will demonstrate macroulceration with mucopurulent exudate and spontaneous hemorrhage
symptoms of UC?
diarrhoea (not present in proctitis)
11. TOXIC COLITIS
The most dangerous acute complication of ulcerative colitis occurs when the ulcerating, inflammatory process dissects deeply through the wall of the colon, producing a serositis and paralytic ileus. An early radiologic sign of this severe “toxic” colitis is an accumulation of gas over a long segment of colon, as seen on plain films of the abdomen (left panel). At this point, the luminal diameter need not be increased; in fact, it may even be narrowed with tubular or scalloped margins due to edema and spasm.
The more classic appearance of toxic dilatation or “megacolon” (right panel) does not usually emerge until late stages of the process, by which time the patient is already in imminent danger of perforation and/or peritonitis. The dilatation is often maximal in the transverse colon because its superior location in the supine patient allows air to collect in this segment of the flaccid bowel. (Rotation of the patient from supine to prone therefore helps redistribute the gas and decompress the colon.) A characteristic radiologic finding demonstrated in this case of toxic dilatation is the protrusion of soft tissue densities into the lumen, representing a combination of pseudopolyps and submucosal edema. The haustra are also abnormal — either obliterated as in this case, or occasionally accentuated. Barium enema and colonoscopy in such patients carry great risks in this situation and are usually contraindicated.
The potentially most lethal complication of toxic colitis is perforation. An early sign of bowel necrosis and impending perforation is subserosal dissection of luminal gas into the bowel wall, visible on this plain film of the abdomen (left panel) as sharply defined linear lucencies paralleling the medial wall of the ascending colon. The CT scan (right panel) demonstrates both a curvilinear air collection in the bowel wall and an adjacent collection of extraluminal air.
Clinical signs and symptoms in such cases may be subtle or absent; even as severe a complication as free perforation of the colon may be clinically silent in patients receiving corticosteroids.
42. COLONOSCOPIC SURVEILLANCE FOR DYSPLASIA
In the search for “early warning signals” of impending malignant transformation, cellular atypia or dysplasia on colonoscopic biopsy has been reported to be a useful sign. Although experience is far from uniform, some series report at least a 50% association of occult malignancy with high-grade dysplasia (lower left panel). For dysplasia to be a reliable warning sign of cancer, however, it is essential that the finding be made independent of severe inflammation (upper left panel). This slide emphasizes the importance, in any program of colonoscopic surveillance for dysplasia, of trying to obtain biopsies from relatively normal areas (solid image in right panel), away from the most grossly inflamed areas of mucosa (dotted image in right panel).
• Riddell RH, Goldman H, Ransohoff DF et al. Dysplasia in inflammatory bowel disease: standardized classification with provisional application. Hum Path 1983;14:931-968.
IBD IBS diff diagnosis?
apthous stomatitis, episcleritis and uveitis, arthritis, vacular complications, E. nodosum. P gangrenosum
54. PERIPHERAL ARTHRITIS
The most common extracolonic manifestation of colitis is a peripheral arthritis that usually affects knees, ankles, wrists, and fingers. The joint inflammation superficially mimics rheumatoid arthritis, but differs in the six principal characteristics listed on the right of the slide. This “colitic arthritis” generally parallels the activity of the underlying inflammatory bowel disease.
• Brynskov J, Binder V. Arthritis and the gut. Eur J Gastroenterol Hepatol 1999;11:997-9.
• Veloso FT, Carvalho J, Magro F. Immune-related systemic manifestations of inflammatory bowel disease: a prospective study of 792 patients. J Clin Gastroenterol 1996;23:29-34.
extra-intestinal complications unrelated to diseae activity
Central (axial) arthropathy:
- Ankylosing spondylitis (associated with HLA B27)
- primary sclerosing cholangitis
55. CENTRAL (AXIAL) ARTHRITIS
Ankylosing spondylitis and sacro-iliitis frequently accompany colitis, although these complications may be detected on x-ray without producing clinical symptoms. In spondylitis, syndes-mophytes bridge the vertebral bodies laterally (AP view, left panel) and anteriorly (lateral view, right panel). Sclerosis of the corners of the vertebral bodies is also visible in the lateral view. The sacro-iliitis results in sclerosis and obliteration of the sacroiliac joints (AP view, left panel).
These central arthritic complications do not parallel the activity of the colitis, but follow an independent course, sometimes preceding the onset of the colitis and often progressing even following total colectomy, as in this case. Note surgical clips showing an ileal pouch or reservoir in the pelvis, proximal to an ileoanal anastomosis. Ankylosing spondylitis and sacro-iliitis tend to occur most often in colitis patients with the HLA haplotype B27.
• de Vlam K, Mielants H, Cuvelier C, De Keyser F, Veys EM, De Vos M. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol 2000;27:2860-5.
60. SCLEROSING CHOLANGITIS
In the film on the left, the changes in the bile ducts are largely confined to the intrahepatic ducts which are distorted, truncated and have segmental areas of narrowing and beading. Isolated intrahepatic ductal involvement on radiologic studies is the presenting manifestation of sclerosing cholangitis in only about 15-20% of cases. Some contrast is seen entering the cystic duct and gallbladder, which is not well filled. The film on the right demonstrates more extensive intrahepatic and extrahepatic biliary involvement with segmental narrowing and dilatation seen in both common bile duct and right hepatic ducts. The left hepatic ducts are not filled out because of a high grade stricture of the duct above the confluence of left and right ducts. Cholecystectomy clips are noted and the pancreatic duct is also filled.
anatomical distribution of crohns?
63. ANATOMIC DISTRIBUTION
Crohn’s disease may affect any part of the alimentary tract from mouth to anus. About one-third of cases are confined to the small bowel (“regional enteritis”), usually involving the terminal ileum (“ileitis”). Nearly half of all cases involve both small and large bowel (“ileocolitis”), usually in continuity. About 20% of cases are confined to the colon alone. Perianal lesions occur in approximately one-third of patients, but are only rarely the presenting or sole site of Crohn’s disease. Oral and gastroduodenal lesions are also commonly found when carefully sought, but are clinically important in only a minority of cases.
clinical patterns of crohns?
64. CLINICAL PATTERNS
Most cases of Crohn’s disease present clinically with local manifestations of intestinal inflammation, but they tend over time to evolve into clinical patterns that are primarily stricturing (obstructive) or penetrating (fistulizing). One common form of penetrating Crohn’s disease appears as an acute microperforation, often resembling an attack of appendicitis.
• Sachar DB, Andrews HA, Farmer RG et al. Proposed classification of patient subgroups in Crohn’s disease. Gastroenterol Internat 1992;5:151-4.
• Gasché C, Scholmerich J, Brynskov J et al. A simple classification of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 1999;6:8-15.
• Kornbluth A, Sachar DB, Salomon P. Crohn’s Disease (Chapter 101). In: Feldman M, Scharschmidt BF, Sleisenger MH eds., Gastrointestinal and Liver Disease, 6th edition (W.B. Saunders, Philadelphia, 1998), pp.1969-1707.
Since Crohn’s disease produces inflammation in the ileocecal region in 75-80% of cases, the most frequent early presentations are with local symptoms of right lower quadrant abdominal pain, tenderness, and diarrhea, frequently with systemic manifestations of low-grade fever, anorexia, and weight loss.
Since the transmural inflammation of Crohn’s disease produces fibromuscular proliferation and collagen deposition in the wall of the intestine leading to narrowing of the lumen, obstructive symptoms are among the most common. Symptoms of partial obstruction are most evident after meals, when luminal distention leads to cramps. Vomiting is the result of high grade obstruction.
Besides wall thickening and obstructive luminal narrowing, another characteristic sequelum of the transmural process in Crohn’s disease is penetrating ulceration through the intestinal wall, culminating in sinus tracts and fistulae to adjacent structures. Clinical symptoms depend on the location of the fistula.
crohns fistular 2?
93. ENTEROVESICAL FISTULA
Since the terminal ileum crosses the dome of the bladder as it traverses the pelvis, the most common form of internal Crohn’s disease fistula, after entero-enteric, is enterovesical. The contrast material in the bladder in this small bowel x-ray is barium that has entered via a fistula from diseased ileum. Dysuria is a frequent symptom and urinary tract infections often result, but one of the earliest and most pathognomonic signs of entero-vesical fistulization is pneumaturia.
• Greenstein AJ, Sachar DB, Tzakis A et al. The course of enterovesical fistulas in Crohn’s disease. Am J Surg 1984;147:788-92.
99. PERIANAL FISTULAE AND ABSCESS
Entirely separate from intra-abdominal Crohn’s disease and from enteric fistulae, an independent focus of disease often arises from the crypts of Morgagni in the anus and spreads through the internal sphincter muscle to give rise to such complications as intersphincteric abscess, ischiorectal abscess, supralevator abscess, and/or rectovaginal or perineal or buttock fistulae. As many as one-third of patients with Crohn’s disease may have a history of anorectal fissures or fistulae or perianal abscesses.
• Buckmann P, Alexander-Williams J. Classification of perianal Crohn’s disease. Clin Gastroenterol 1980;9:323-330.
73. X-RAY APPEARANCE OF ILEITIS
The transmural inflammation and lymphoid proliferation of Crohn’s disease, characteristically affecting the terminal ileum, account for the typical radiologic features of nodularity, ulceration, and narrowing and irregularity of the lumen (right panel). Separation of normal from involved loops of intestine reflects luminal narrowing, thickening of bowel wall, and mesenteric hypertrophy. A combination of transmural thickening and irritative spasm produces the classical “string sign” in the terminal ileum (left panel).
83. TRANSMURAL INFLAMMATION
The key to understanding the course and complications of Crohn’s disease lies in recognizing the nature of the transmural pathology. While the mucosal ulceration may be patchy, the inflammatory process characteristically extends through all layers of the bowel wall, all the way to the serosa. Inflammatory infiltration, edema, fibrosis, and spasm combine to produce marked narrowing of the lumen, often leading to obstruction, while deeply penetrating sinus tracts may culminate in frank fistulization.
distinguishing features of CD?
105. DISTINGUISHING FEATURES OF CROHN’S DISEASE
In most cases, Crohn’s disease of the colon is readily distinguished from ulcerative colitis by clinical, radiologic, endoscopic, and pathologic features. The great majority of cases (70-85%) of Crohn’s colitis have small bowel involvement and relative sparing of the rectum. Although most patients have some gross rectal bleeding, a substantial minority (25-30%) note no blood; this absence of bleeding, by contrast, is almost never reported in ulcerative colitis. Except for small rectovaginal fistulae, which are sometimes seen in ulcerative colitis, major perianal lesions in IBD are a feature exclusively of Crohn’s disease. Other characteristics of the lesions of Crohn’s disease, as distinguished from ulcerative colitis, are locality in the setting of relatively normal intervening mucosa, segmental rather than diffuse or continuous distribution, and asymmetric involvement of different parts of the wall within given segments of bowel. Fistulization into surrounding tissues and organs occurs only in Crohn’s disease as opposed to ulcerative colitis. Granulomas or “microgranulomas” may be found on careful study of Crohn’s disease rectal biopsies in 25-30%, and in surgical specimens in up to 50-75% of cases; they are not necessary to establish a diagnosis of Crohn’s disease, but when present they are virtually pathognomonic.
• Lockhart-Mummery HE, Morson BC. Crohn’s disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1960;1:87-105.
• Wolf BS, Marshak RH. Granulomatous colitis (Crohn’s disease of the colon): Roentgen features. Am J Roentgenol 1962;88:662-670.
• Lindner AE, Marshak RH, Wolf BS et al. Granulomatous colitis—a clinical study. N Engl J Med 1963;269:379-385.
• Marshak RH, LindnerAE, Janowitz HD. Granulomatous ileecolitis. Gut 1966;7:258-264.
• Farmer RG, Hawk WA, Turnbull RB. Regional enteritis of the colon: Clinical and pathological comparison with ulcerative colitis. Am J Dig Dis 1968;13:501-14.
• Lennard-Jones JE, Lockhart-Mummery HE, Morson BC. Clinical and pathological differentiation of Crohn’s disease and proctocolitis. Gastroenterology 1968;64:1162-1170.
• Cook MG, Dixon MF. An analysis of the reliability of detection and diagnostic value of various patholegic features in Crohn’s disease and ulcerative colitis. Gut 1973;14:255-62.
• Waye JD. The role of colonoscopy in the differential diagnosis of inflammatory bowel disease. Gastrointest Endosc 1977;23:150-4.
ibd risk factors?
Intestinal barrier function
Mucosal response to luminal bacteria
Downstream immune responses
169. SULFASALAZINE METABOLISM
Once sulfasalazine is ingested, about 30% of the intact molecule is absorbed from the upper GI tract either to be carried in the entero-hepatic circulation or to be excreted by the kidneys. Almost 90% of the intact sulfasalazine molecule ultimately passes down to the lower GI tract, where intestinal bacterial enzymes cleave the azo bond, thus releasing sulfapyridine and 5-ASA. Most of the sulfapyridine is absorbed, metabolized by the liver, and excreted in the urine. It is the circulating sulfapyridine that is responsible for the principle clinical toxicity, especially in patients who are slow acetylators. Meanwhile, the 5-ASA stays primarily in the bowel lumen, where it is thought to exert its therapeutic effects locally prior to elimination in the feces.
• Schroder H, Campbell DES. Absorption, metabolism, and excretion of the salicylazosulfapyridine in man. Clin Pharmacol Ther 1972;13:539-51.
• Peppercorn MA, Goldman P. The role of intestinal bacteria in the metabolism of salicylazosulfapyridine. J Pharmacol Exp Ther 197
The development of newer aminosalicylates is based upon efforts to deliver active 5-ASA to the lower GI tract while avoiding the toxicity of sulfapyridine, which is present in sulfasalazine. Suspensions and suppositories of 5-ASA are instilled directly into the rectum (right side of the slide). Oral preparations (left side of the slide) include (1) enteric coated and ethylcellulose encapsulated forms of 5-ASA (mesalamine), or (2) 5-ASA linked by a di-azo bond to a non-toxic polymer (balsalazide), or (3) a dimer of 5-ASA (olsalazine) that is split by intestinal bacterial azo-reductases into two molecules of 5-ASA with no toxic or inert moiety remaining.
Mild to moderate UC Mesalazine
Severe UC Corticosteroids (Ciclosporin/IFX)
Maintenance of remission
221. SURGICAL OPTIONS IN ULCERATIVE COLITIS
Until the last one or two decades, the conventional operation for ulcerative colitis was a standard Brooke ileostomy. The operation is curative and requires no anastomosis to heal, but it does result in permanent fecal incontinence and requires the wearing of an external appliance. A continent ileostomy can be fashioned from an ileal-reservoir with a nipple valve (Kock pouch). No external appliance is needed, but emptying requires regular catheterization through the nipple valve. Complications include pouchitis and nipple malfunction leading to incontinence.
The ileal pouch-anal anastomosis (IPAA) is a sphincter-saving operation that allows anal continence with an overall 95% chance of success. Complications of this procedure include anastomotic leaks, stricture formation, pouchitis, and partial incontinence. In a limited group of patients with relatively mild distal disease, a straight ileo-rectal anastomosis can be considered. Such patients require ongoing cancer surveillance of the remaining rectal segment.
• Becker JM. Indications for colectomy and choice of procedures. In: BaylessTM, Hanauer SB. eds. Advanced Therapy of Inflammatory Bowel Disease. London, BC Decker Inc., 2001;175-178.
• Pastore RL, Wolff BG, Hodge D. Total abdominal colectomy and ileo- rectal anastomosis for inflammatory bowel disease. Dis Colon Rectum 1997;40:1455-64.
• Kock NG. Continent ileostomy. Prog Surg 1973;12:180.
Mild to moderate: Budesonide
Severe Corticosteroids Infliximab/adalimumab
Maintenance of remission
corticosrerois i IBD?
Budesonide (controlled ileal release)
Enema and suppository
azothipprine and mercaptopurione?
195. AZATHIOPRINE AND 6-MERCAPTOPURINE
Azathioprine is a pro drug that is quickly converted to 6-mercaptopurine via a non-enzymatic nucleophilic attack by sulfhydryl-containing compounds such as glutathione present in red blood cells and other tissues. These purine-antagonist anti-metabolites interfere with nucleic acid synthesis in white blood cells, especially in T-lymphocytes, which are important in the production of mediators of inflammation.
other immunosuppressive drugs?
infliximab 75% human (25% mouse)
certolizumab pegol (humand and mouse)
adalimumab (90% human)
post op recurrent rates?
112. POSTOPERATIVE RECURRENCE RATES IN CROHN’S DISEASE
Eighty-nine patients treated by ileal resection for Crohn’s disease were followed prospectively to determine rates of reoperation, symptomatic relapse, and endoscopic recurrence. In a six-year follow-up period only 15% of patients were free of endoscopic recurrence with 73% having developed lesions within the first year. In the first three years of follow-up, 66% of patients had not developed clinical symptoms; by eight years, 40% were still free of symptomatic recurrence. Seventy-one of the 89 patients (80%) had not required further resection after eight years. The post-operative clinical course was best predicted by the severity of endoscopic lesions of Crohn’s disease during the first year after resection. Those with endoscopic evidence of diffuse recurrent lesions in the neo-terminal ileum within one year of resection tended to get early symptoms and complications.
• Rutgeerts P, Geboes K, van Trappen G et al. Predictability of the postoperative course