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  1. 1. <ul><li>DEFINITION </li></ul><ul><li>TWO COMMMON DISORDER </li></ul><ul><li>INCIDENCE OF IBD </li></ul>
  2. 2. DEFINITION <ul><ul><li>inflammatory bowel disease describes a chronic condition of intestinal inflammation and ulceration that has no identifiable cause </li></ul></ul>
  3. 3. <ul><li>DEFINITION </li></ul><ul><li>TWO COMMMON DISORDER </li></ul><ul><li>INCIDENCE OF IBD </li></ul>
  4. 4. <ul><li>Crohn’s disease </li></ul><ul><li>Ulcerative colitis </li></ul>
  5. 5. <ul><li>Crohn's disease is an ongoing disease of the digestive or gastrointestinal (GI) tract. </li></ul><ul><li>The hallmarks of Crohn's disease are swelling of the GI tract,abdominal pain, and frequent diarrhea. </li></ul><ul><li>The condition can affect any area of the GI tract, from the mouth to the anus, including esophagus, stomach, small intestine, large intestine, and rectum. </li></ul><ul><li>It most commonly affects the ileum, the lower portion of the small intestine. </li></ul>
  6. 7. <ul><li>Crohn’s disease </li></ul><ul><li>Ulcerative colitis </li></ul>
  7. 8. <ul><li>Ulcerative colitis is a chronic, ongoing disease of the lower digestive or gastrointestinal (GI) tract. </li></ul><ul><li>The hallmarks of ulcerative colitis are abdominal pain and bloody diarrhea due to inflammation and the development of open sores (ulcers) in the large intestine (colon) and rectum. </li></ul>
  8. 9. <ul><li>Ulcerative colitis is categorized according to location: </li></ul><ul><li>Proctitis involves only the rectum </li></ul><ul><li>Proctosigmoiditis affects the rectum and sigmoid colon </li></ul><ul><li>Left-sided colitis encompasses the entire left side of the large intestine </li></ul><ul><li>Pancolitis inflames the entire colon </li></ul>
  9. 10. INCIDENCE <ul><li>Ulcerative colitis occurs in 35–100 people for every 100,000 in the United States, or less than 0.1% of the population. </li></ul><ul><li>The disease is more prevalent in northern countries of the world. </li></ul>
  10. 11. INCIDENCE <ul><li>About 7 of every 100,000 people in US have Crohn's disease. </li></ul><ul><li>These are among the highest rates in the world. </li></ul><ul><li>The incidence is about 1-3 per 100,000 in southern Europe, South Africa, and Australia, and is even lower, less than 1 per 100,000, in Asia and South America. </li></ul>
  11. 12. Environment Triggers Immunoregulatory Defects and Microbial Exposure Genetic Factor c)Occupation a)Dysfunctional immune host response to normal luminal components a)Westernization b)Sanitation and exposure to infection d)Diet c)Defective barrier function IBD-1 locus and NOD2/CARD15 gene e)Tobacco smoking b)Infection with a specific pathogen Etiology
  12. 13. Westernization <ul><li>IBD is most prevalent in developed regions, including the United States and United Kingdom </li></ul><ul><li>This may also account for the north-to-south variation and higher frequency in urban communities compared with rural areas. </li></ul><ul><li>increases in incidence have recently been noted in southern countries and Asia and among migrants to first-world countries </li></ul><ul><li>this is the result of ‘‘westernization’’ of lifestyle, such as changes in diet, smoking, and variances in exposure to sunlight, pollution, and industrial chemicals </li></ul>
  13. 14. Sanitation and exposure to infection <ul><li>IBD is a disease of cleanliness </li></ul><ul><li>Is common with diseases such as asthma, multiple sclerosis, and rheumatoid arthritis </li></ul><ul><li>it demonstrates an inverse relationship with the degree of sanitation </li></ul><ul><li>poor sanitation appears to protect against IBD </li></ul><ul><li>overcrowding may also be a factor </li></ul><ul><li>For example, children raised in more spacious conditions (reduced sharing of sleeping accommodation and bathrooms) have a higher risk of developing CD </li></ul><ul><li>It is postulated that improved hygiene alters the intestinal flora by decreasing exposure to certain critical bacteria. </li></ul><ul><li>There is also an increased frequency of UC and CD in higher socioeconomic groups. </li></ul>
  14. 15. Occupation <ul><li>Both UC and CD are more prevalent in white-collar compared with blue-collar occupations. </li></ul><ul><li>Higher mortality from IBD has been noted in managerial, clerical, and sales positions, which typically involve sedentary, indoor work. </li></ul><ul><li>In contrast, mortality resulting from IBD is low among farmers and construction workers. </li></ul><ul><li>outdoor air and physical activity is protective against IBD, whereas work in artificial venues confers an increased risk. </li></ul><ul><li>This theory could explain the higher risk for IBD in northern climates (e.g., more indoor exposure) and in immigrants to developed countries, as well as the varying rates among ethnic groups in different regions. </li></ul>
  15. 16. Diet <ul><li>Studies seeking to link diet and IBD are generally inconclusive. </li></ul><ul><li>There is some evidence that a higher intake of fatty acids increases the risk for IBD </li></ul><ul><li>frequent fast-food intake confers a 3- to 4-fold greater risk for IBD. </li></ul>
  16. 17. Tobacco smoking <ul><li>The strongest environmental risk factor for IBD </li></ul><ul><li>Numerous case-control studies have shown that current smoking is protective against UC (relative risk [RR], 40% of that of nonsmokers), with results that are consistent across diverse geographic regions. </li></ul><ul><li>The decreased risk for UC in smokers appears to be dose dependent </li></ul><ul><li>Paradoxically, ex-smokers are approximately 1.7 times more likely to develop UC than those who never smoked. </li></ul><ul><li>Ex-smokers also have a poorer disease course, with more frequent hospitalization than current smokers </li></ul><ul><li>as a group they are twice as likely as current smokers and those who have never smoked to require colectomy </li></ul>
  17. 18. <ul><li>In contrast to UC, cigarette smoking is a significant risk factor for the development of CD </li></ul><ul><li>Smokers with CD have a poorer disease course than nonsmokers, with higher disease recurrence, more frequent surgical interventions, and a greater need for immunosuppressive agents. </li></ul><ul><li>An exception is provided by Jewish patients living in Israel, in whom smoking is not associated with an increased risk of developing CD </li></ul><ul><li>Interestingly, smoking continues to protect this group against UC, suggesting that genetic factors may override environmental influences </li></ul>
  18. 19. Genetic Factor IBD-1 locus and NOD2/CARD15 gene <ul><li>microsatellite DNA markers identified several genetic sites as being potentially associated with UC or CD. </li></ul><ul><li>Significant linkages have been reported on chromosomes 1, 3, 6, 7, 12, 14, 16, and 19 </li></ul><ul><li>the clearest linkages is for IBD-1, a susceptibility locus in the pericentromeric region of chromosome 16 </li></ul><ul><li>analysis has resulted in the identification of the nucleotide-binding oligomerization domain 2 (NOD2) gene and protein. </li></ul><ul><li>NOD2 also known as- caspase activation and recruitment domain 15 (CARD15) </li></ul><ul><li>This is a polymorphic gene, the product of which is involved in the innate immune system. </li></ul><ul><li>It is the first gene to be clearly associated with IBD, and >60 mutations have been recognized, 3 of which have been linked to the development of CD. </li></ul>
  19. 20. <ul><li>The NOD2 gene is expressed mainly in monocyte/macrophage cell lines, where it has a role in host-signaling pathways </li></ul><ul><li>One effect is the activation of nuclear factor (NF)-kB, a transcription factor involved in cellular inflammatory responses and macrophage apoptosis </li></ul><ul><li>Activation leads to production of a wide variety of nonspecific mediators of inflammation </li></ul><ul><li>which facilitate the inflammatory process and lead to tissue destruction </li></ul><ul><li>The trigger for NF-kB appears to be the presence of lipopolysaccharide, a cell wall component found in Gram-negative bacteria </li></ul><ul><li>Mutations in the NOD2 gene paradoxically reduce macrophage activation of NF-kB </li></ul><ul><li>Consequently, one may expect diminished inflammation rather than the increase seen in IBD </li></ul>
  20. 21. <ul><li>the NOD2 mutation may increase susceptibility to chronic intracellular infection or prevent the development of tolerance to commensal microflora </li></ul><ul><li>In the absence of NOD2 expression by epithelial cells, microbial products that normally induce these cells to secrete chemokines fail to do so, leading to proliferation of bacteria and potential loss of barrier function </li></ul>
  21. 22. Immunoregulatory Defects and Microbial Exposure <ul><li>In healthy gut epithelium, the presence of potentially proinflammatory luminal bacteria is tolerated without neutrophil recruitment into the epithelial surface </li></ul><ul><li>This may be caused in part by the unique phenotype of the resident macrophage population within the intestine </li></ul><ul><li>Triggering the receptor expressed on myeloid cells (TREM-1) is a cell surface molecule present on neutrophils, monocytes, and macrophages that amplifies the inflammatory response by enhancing degranulation and secretion of proinflammatory cytokines </li></ul><ul><li>Theories suggested concerning the pathogenesis of this process: </li></ul><ul><li>dysfunctional immune host response to normal luminal components, </li></ul><ul><li>infection with a specific pathogen </li></ul><ul><li>defective mucosal barrier to luminal antigens. </li></ul>
  22. 23. a) Dysfunctional immune host response to normal luminal components <ul><li>normal relationship between commensal bacteria and the host is symbiotic </li></ul><ul><li>It is hypothesized that exposure to commensal bacteria down-regulates the inflammatory genes and blocks activation of the NF-kB pathway, thus inhibiting the inflammatory immune response of the gut to the myriad microbes and food antigens to which it is constantly exposed </li></ul><ul><li>In IBD, this tolerance is lost </li></ul><ul><li>Exposure to luminal microflora now triggers an inflammatory response by the cells lining the mucosa, leading to a chronic, destructive immune response </li></ul>
  23. 24. b) Infection with a specific pathogen <ul><li>To date, no single organism has been conclusively associated with the development of IBD </li></ul><ul><li>Implicated pathogens include Mycobacterium paratuberculosis, M paramyxovirus, Listeria monocytogenes, and Helicobacter hepaticus </li></ul>
  24. 25. <ul><li>Variance in bacterial activation of the inflammatory immune response. </li></ul><ul><li>Antiinflammatory commensal bacteria (nonvirulent Salmonella strains) inhibit the NF-kB pathway via blockade of the inhibitor of NF-kB (IkB)–a degradation, which prevents subsequent nuclear translocation of the active NF-kB dimer </li></ul><ul><li>Although phosphorylation of IkB-a occurs, the subsequent polyubiquitination required for regulated IkB-a degradation is abrogated </li></ul><ul><li>Pathogenic bacteria activate the NF-kB pathway. </li></ul><ul><li>The bacteria bind to a cell-surface receptor, the toll-like receptor (TLR), which generates inflammatory factors connected to the NF-kB pathway. </li></ul><ul><li>They stimulate intermediate kinases, leading to phosphorylation (P) of the inhibitor of B kinase (IKK) and subsequent dissociation of NF-kB. </li></ul><ul><li>NF-kB is then able to travel to the nucleus, where it turns on inflammatory </li></ul><ul><li>genes. </li></ul><ul><li>IRAK = IL-IR–associated kinase </li></ul><ul><li>MyD88 = myeloid differentiation factor 88 </li></ul><ul><li>TIR domain = toll/interleukin-1 receptor </li></ul><ul><li>UBQ = ubiquitination </li></ul>
  25. 26. c) Defective barrier function <ul><li>IBD is associated with increased permeability of the epithelial lining of the gut resulting in continuous stimulation of the mucosal immune system </li></ul><ul><li>It has been suggested that this may be the primary defect in individuals with IBD </li></ul><ul><li>Animal studies show a tendency for the development of severe inflammation in areas of the intestine lying beneath the permeability defect </li></ul><ul><li>Luminal bacteria appear to intensify the permeability defect further, establishing a self-sustaining cycle of mucosal inflammation that allows for uptake and translocation of bacteria </li></ul><ul><li>In humans, the lumen typically contain 1014 organisms belonging to 30 known genera and >500 species </li></ul><ul><li>Healthy epithelium, with its highly evolved tight junctions, normally provides an effective barrier against luminal microbes and antigens </li></ul><ul><li>Also, the intestinal epithelial cells have developed control mechanisms that limit inappropriate activation of immune responses </li></ul>
  26. 27. <ul><li>If, however, bacterial products are able to cross the mucosal barrier, then they will come into direct contact with immune cells, resulting in a classic adaptive immune response </li></ul><ul><li>Avariety of inflammatory cytokines are produced, recruiting additional cells into the intestine wall </li></ul><ul><li>These include cytokines that reduce the tight junctions between the endothelial cells in the gut vasculature, which in turn facilitates recruitment of neutrophils to the mucosa from the peripheral blood </li></ul>
  27. 28. Pathologic Findings in IBD
  28. 29. Ulcerative colitis <ul><li>Morphology. </li></ul><ul><li>Ulcerative colitis involves the rectum and extends proximally in a retrograde fashion to involve the entire colon (&quot;pancolitis&quot;) in the more severe cases. </li></ul><ul><li>In contrast to CD, the ileitis is often diffuse and limited to within 25 cm from the ileocecal valve. The appendix may be involved with both CD and UC </li></ul>
  29. 30. CROHN DISEASE <ul><li>When fully developed, Crohn disease is characterized pathologically by </li></ul><ul><li>(1) sharply delimited and typically transmural involvement of the </li></ul><ul><li>bowel by an inflammatory process with mucosal damage </li></ul><ul><li>(2) the presence of noncaseating granulomas </li></ul><ul><li>(3) fissuring with formation of fistulae. </li></ul>
  30. 31. Morphology. <ul><li>In CD, there is gross involvement of the small intestine alone in about 40% </li></ul><ul><li>colon alone in about 30%. </li></ul><ul><li>duodenum, stomach, esophagus, and mouth, are distinctly uncommon sites. </li></ul><ul><li>The serosa is granular and dull gray, and often the mesenteric fat wraps around the bowel surface (creeping fat). </li></ul><ul><li>The intestinal wall is rubbery and thick, caused by edema, inflammation, fibrosis, and hypertrophy of the muscularis propria. </li></ul><ul><li>As a result, the lumen is almost always narrowed; in the small intestine this is evidenced on x-ray as the &quot;string sign,&quot; a thin stream of barium passing through the diseased segment. </li></ul><ul><li>A classic feature of CD is the sharp demarcation of diseased bowel segments from adjacent uninvolved bowel. </li></ul>
  31. 32. Endoscopic image of colon cancer identified in the sigmoid colon on screening colonoscopy for Crohn's disease.
  32. 33. Crohn's disease can mimic ulcerative colitis on endoscopy. This endoscopic image is of Crohn's colitis showing diffuse loss of mucosal architecture, friability of mucosa in sigmoid colon and exudate on wall, all of which can be found with ulcerative colitis.
  33. 34. Section of colectomy showing transmural inflammation
  34. 35. Endoscopy image of colon showing serpiginous ulcer, a classic finding in Crohn's disease
  35. 36. Ulcerative Collitis <ul><li>A key feature of UC is that the mucosal damage is continuous from the rectum and extending proximally. In CD, mucosal damage in the colon may be continuous but is just as likely to exhibit skip areas. It should be noted that quiescent UC, particularly treated disease in which active neutrophilic inflammation is not present, may appear virtually normal histologically. </li></ul>
  36. 37. Endoscopic image of a sigmoid colon afflicted with ulcerative colitis. Note the vascular pattern of the colon granularity and focal friability of the
  37. 38. Colonic pseudopolyps of a patient with intractable ulcerative colitis . Colectomy specimen
  38. 39. H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis
  39. 40. Biopsy sample ( H&E stain ) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.
  40. 41. SIGN & SYMPTOM of IBD
  41. 42. Inflammatory Bowel Disease Symptoms Because inflammatory bowel disease is a chronic disease (lasting a long time), you will go through periods in which the disease flares up and causes symptoms. These periods are followed by remission, in which symptoms disappear or decrease and good health returns. Symptoms may range from mild to severe and generally depend upon the part of the intestinal tract involved. They include the following :
  42. 43. Abdominal cramps and pain Bloody diarrhea Severe urgency to have a bowel movement Fever Loss of appetite Weight loss Anemia (due to blood loss)
  43. 44. Other Symptoms of IBD People with IBD may have symptoms outside the digestive tract, such as: Mouth sores and skin problems Arthritis Eye problems that affect vision
  44. 45. Symptoms in Crohn's disease vs. ulcerative colitis Crohn's disease Ulcerative colitis Defecation Often porridge-like sometimes steatorrhea Often mucus-like and with blood Tenesmus Less common More common Fever Common Indicates severe disease Fistulae Common Seldom Weight loss Often More seldom
  45. 46. Findings in diagnostic workup in Crohn's disease vs. ulcerative colitis Sign Crohn's disease Ulcerative colitis Terminal ileum involvement Commonly Seldom Colon involvement Usually Always Rectum involvement Seldom Usually Involvement around the anus Common Seldom Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate
  46. 47. Distribution of Disease Patchy areas of inflammation (Skip lesions) Continuous area of inflammation Endoscopy Deep geographic and serpiginous (snake-like) ulcers Continuous ulcer Depth of inflammation May be transmural, deep into tissues Shallow, mucosal Stenosis Common Seldom Granulomas on biopsy May have non-necrotizing non-peri-intestinal crypt granulomas Non-peri-intestinal crypt granulomas not seen Sign Crohn's disease Ulcerative colitis
  47. 48. Pathological features of Crohn’s disease Any portion of small bowel: usually ileum may also involve: any segment of digestive tract Early stages: involved small bowel has soggy feeling mucosa: reddish purple may show pinpoint erosions known as ‘aphthoid ulcers’ Later stages: prominent ulceration
  48. 49. EARLY STAGE <ul><li>So-called ‘aphthoid ulcers’, an early feature of Crohn's disease. </li></ul>Fig. 1:  Gross appearance of Crohn's disease. There is a sharp demarcation between the involved and the uninvolved areas.
  49. 50. Fig. 2:  Gross appearance of Crohn's disease. The combination of ulceration and elevated remnants of mucosa results in a typical cobblestone appearance. Fig. 3:  Gross appearance of Crohn's disease. Another example of cobblestone appearance. Fig. 4:  Gross appearance of Crohn's disease. Note the segmental nature of the inflammation, and rigidity of the wall, and flattening of the mucosa are characteristic.
  50. 51. Histopathology Submucosal lymphedema: early change accompanied by: lymphoid hyperplasia in lamina propria and submucosa scattering of chronic inflammatory cells, including: plasma cells: including some binucleated forms lymphocytes eosinophils Histiocytes: some containing prominent lysosomal inclusions mast cells Ulcerations: begin at top of lymphoid follicles preceded by patchy epithelial necrosis may have vascular pathogenesis
  51. 52. <ul><li>Fissures with slitlike formations: </li></ul><ul><li>with: </li></ul><ul><li>sharp edges </li></ul><ul><li>narrow lumina </li></ul><ul><li>arranged perpendicularly to mucosa </li></ul><ul><li>extend deep into submucosa and even muscularis externa </li></ul>
  52. 53. Crohn's disease <ul><li>  Crohn's disease showing marked inflammatory changes and the formation of a fissure. </li></ul>
  53. 54. <ul><li>Nonulcerated mucosa: </li></ul><ul><li>usually combination of atrophy and regenerative hyperplasia </li></ul><ul><li>May be foci of pyloric metaplasia </li></ul><ul><li>Well-developed disease: </li></ul><ul><ul><li>nearly always transmural: </li></ul></ul><ul><ul><ul><li>changes much more severe in submucosa and subserosa than in muscularis externa </li></ul></ul></ul><ul><ul><ul><ul><li>edema </li></ul></ul></ul></ul><ul><ul><ul><ul><li>lymphatic dilatation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>hyperemia: </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>usually mild to moderate </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>hyperplasia of muscularis mucosae </li></ul></ul></ul></ul><ul><ul><ul><ul><li>fibrosis </li></ul></ul></ul></ul><ul><li>Inflammatory changes may involve walls of veins and arteries 6 </li></ul><ul><li>Increase in number of smooth muscle fibers in submucosa: </li></ul><ul><ul><li>‘ obliterative muscularization’ </li></ul></ul><ul><ul><li>may contribute to development of obstruction </li></ul></ul>
  54. 55. <ul><li>Whole mount specimen of Crohn's disease showing transmural inflammation with predominance of the inflammation in the mucosa and submucosa. </li></ul>
  55. 56. Signs and symptoms Diarrhea- patients often experience frequent loose or watery bowel movements. -stool is occasionally accompanied by thick, dark blood (not bright red smears of blood, which usually result from a bleeding hemorrhoid) -There is less mucus or pus in the stool than in cases of ulcerative colitis.
  56. 57. Pain <ul><li>Patients may experience crampy, achy, or even sharp pain in the affected area. </li></ul><ul><li>Most often, patients with Crohn's disease feel pain on the lower right side of the abdomen (lower right quadrant) and just below the bellybutton- because the majority of cases of Crohn's disease involve disease in the terminal ileum, where the small intestine meets the large intestine. </li></ul><ul><li>terminal ileum crosses from left to right just above the beltline, and joins the large intestine in the lower right quadrant. </li></ul><ul><li>pain associated with Crohn's disease depends on what part of the GI tract is affected. </li></ul><ul><li>Disease in the terminal ileum generally causes sharp pain, while disease in the colon causes more crampy pain, similar to that that of ulcerative colitis. Pain is sometimes relieved (temporarily) after a bowel movement. </li></ul>
  57. 58. Fever <ul><li>Crohn's is an inflammatory disease, and one of the key characteristics of the inflammatory process is fever. </li></ul><ul><li>Some individuals with Crohn's disease suffer a high fever, especially during the acute phase of a flare-up </li></ul><ul><li>Others run a persistent, low-grade fever. Fever may be accompanied by irritability and fatigue. </li></ul><ul><li>fever recurs each day, especially late in the day, then repeatedly breaks during sleep, causing night sweats. </li></ul>
  58. 59. Signs and Symptoms Unrelated To The GI Tract <ul><li>Reddening and inflammation of the eye (iritis) </li></ul><ul><li>Joint pain (usually in the large joints of the knees, ankles, elbows, wrists, and shoulders), which sometimes migrates from one joint to another (migrating arthralgia) </li></ul><ul><li>Skin lesions, including tender red nodules on the shins or calves (erythema nodosum) </li></ul><ul><li>Sores inside the mouth (aphthous ulcers) </li></ul>
  59. 60. Complications <ul><li>blockage of the intestine - Blockage occurs because the disease tends to thicken the intestinal wall with swelling and scar tissue, narrowing the passage. </li></ul><ul><li>may also cause sores, or ulcers, that tunnel through the affected area into surrounding tissues, such as the bladder, vagina, or skin. </li></ul><ul><li>areas around the anus and rectum are often involved. The tunnels, called fistulas, are a common complication and often become infected. </li></ul><ul><li>addition to fistulas, small tears called fissures may develop in the lining of the mucus membrane of the anus. </li></ul>
  60. 61. <ul><li>Nutritional complications are common -Deficiencies of proteins, calories, and vitamins </li></ul><ul><li>deficiencies may be caused by inadequate dietary intake, intestinal loss of protein, or poor absorption, also referred to as malabsorption. </li></ul><ul><li>Other complications include arthritis, skin problems, inflammation in the eyes or mouth, kidney stones, gallstones, or other diseases of the liver and biliary system </li></ul>
  61. 62. Pathological features of Ulcerative colitis <ul><li>Location: </li></ul><ul><ul><li>characteristically left sided: </li></ul></ul><ul><ul><ul><li>usually: </li></ul></ul></ul><ul><ul><ul><ul><li>begins in rectosigmoid area </li></ul></ul></ul></ul><ul><ul><ul><ul><li>spreads proximally: </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>sometimes entire colon (pancolitis) </li></ul></ul></ul></ul></ul><ul><ul><ul><li>sometimes localized to rectum (ulcerative proctitis 25 ) </li></ul></ul></ul><ul><li>Appearance varies with stage 26 </li></ul><ul><li>May involve: </li></ul><ul><ul><li>ileum </li></ul></ul><ul><ul><li>appendix </li></ul></ul><ul><li>anal canal </li></ul>
  62. 63. <ul><li>Acute Stage </li></ul><ul><li>Mucosal surface: </li></ul><ul><ul><li>wet and glaring from blood and mucus </li></ul></ul><ul><ul><li>Often petechial hemorrhages </li></ul></ul>Fig. 1:  Ulcerative colitis. Acute form with marked hyperemia.
  63. 64. Chronic Stage <ul><li>Various-sized ulcers of irregular configuration </li></ul><ul><ul><li>some undermine mucosa resulting in mucosal bridges with underlying inflammatory infiltrate </li></ul></ul><ul><li>Elevated sessile reddish nodules: </li></ul><ul><ul><li>known as pseudopolyps </li></ul></ul><ul><li>often in otherwise flat surface </li></ul><ul><ul><li>typically: </li></ul></ul><ul><ul><ul><li>small </li></ul></ul></ul><ul><ul><ul><li>multiple </li></ul></ul></ul><ul><ul><li>rarely filiform configuration </li></ul></ul><ul><ul><li>sometimes giant size: </li></ul></ul><ul><ul><ul><li>raise suspicion of carcinoma </li></ul></ul></ul>
  64. 65. Fig. 2:  Ulcerative colitis. Chronic form, showing mucosal ulceration with residual foci of elevated and hyperemic mucosa. Fig. 3:  Pseudopolyps in ulcerative colitis. Fig. 4:  Pseudopolyps in ulcerative colitis.
  65. 66. More Advanced Stage <ul><li>Entire bowel: </li></ul><ul><ul><li>fibrotic </li></ul></ul><ul><ul><li>narrowed </li></ul></ul><ul><ul><li>shortened </li></ul></ul><ul><li>If colon defunctionalized with ileostomy or colostomy before colectomy, may be: </li></ul><ul><ul><li>extreme narrowing of lumen </li></ul></ul><ul><ul><li>great atrophy of all components of wall </li></ul></ul><ul><ul><li>marked increase in pericolic fat </li></ul></ul>Fig. 5:  Ulcerative colitis. Late stage, showing total mucosal atrophy.
  66. 67. Quiescent Stage <ul><li>No ulceration </li></ul><ul><li>Mucosa: </li></ul><ul><ul><li>atrophic </li></ul></ul><ul><ul><li>sometimes appears grossly normal </li></ul></ul><ul><li>May be extensive submucosal fat deposition </li></ul>
  67. 68. Histopathology <ul><li>Primarily a mucosal and submucosal disease. </li></ul><ul><li>Acute Stage </li></ul><ul><li>Inflammatory Infiltrate </li></ul><ul><li>Increased number of inflammatory cells in lamina propria: </li></ul><ul><li>Accumulation of neutrophils at base of crypts: </li></ul><ul><ul><li>result in crypt abscesses </li></ul></ul><ul><li>Inflammatory cells in stroma comprise: </li></ul><ul><ul><li>neutrophils </li></ul></ul><ul><ul><li>lymphocytes: many activated T lymphocytes </li></ul></ul><ul><ul><li>plasma cells: a polyclonal population of IgG-, IgM-, and IgA-producing cells </li></ul></ul><ul><ul><li>a few histiocytes </li></ul></ul><ul><ul><li>other accessory cells </li></ul></ul><ul><ul><li>scattered eosinophils </li></ul></ul><ul><ul><li>mast cells: said to accumulate at line of demarcation between normal and abnormal mucosa </li></ul></ul>
  68. 69. <ul><li>No granulomas containing epithelioid and multinucleated giant cells: </li></ul><ul><ul><li>important criterion in differential diagnosis with Crohn's disease: </li></ul></ul><ul><li>May be: </li></ul><ul><ul><li>crypt-associated intramucosal granulomas due to crypt rupture </li></ul></ul><ul><ul><li>numerous lymphoid follicles: </li></ul></ul><ul><ul><ul><li>particularly in rectum </li></ul></ul></ul><ul><ul><ul><li>may lead to marked distortion of crypts </li></ul></ul></ul><ul><li>Glands </li></ul><ul><li>Progressively destroyed </li></ul><ul><li>Marked decrease in cytoplasmic mucus: </li></ul><ul><ul><li>accompanied by alteration in a particular species of mucin: </li></ul></ul><ul><ul><ul><li>some postulate a specific mucin defect </li></ul></ul></ul><ul><li>Irregular shapes from combination of: </li></ul><ul><ul><li>atrophic changes </li></ul></ul><ul><ul><li>regenerative changes: </li></ul></ul><ul><ul><ul><li>also manifested by: </li></ul></ul></ul><ul><ul><ul><ul><li>nuclear enlargement </li></ul></ul></ul></ul><ul><ul><ul><ul><li>increased mitotic activity not limited to lower portion of crypts </li></ul></ul></ul></ul><ul><li>Paneth cells: </li></ul><ul><ul><li>expression of metaplasia </li></ul></ul>
  69. 70. Quiescent Stage <ul><li>Mucosa: </li></ul><ul><ul><li>subtle abnormalities: </li></ul></ul><ul><ul><ul><li>branching and irregular glands </li></ul></ul></ul><ul><ul><ul><li>gap between base of crypts and muscularis mucosae </li></ul></ul></ul><ul><ul><ul><li>Paneth cells </li></ul></ul></ul><ul><ul><ul><li>hyperplasia of endocrine cells </li></ul></ul></ul><ul><ul><ul><li>more than occasional neutrophils </li></ul></ul></ul><ul><ul><ul><li>islands of lipocytes in lamina propria </li></ul></ul></ul><ul><ul><li>changes can be very mild: </li></ul></ul><ul><ul><ul><li>particularly if: </li></ul></ul></ul><ul><ul><ul><ul><li>a child </li></ul></ul></ul></ul><ul><ul><ul><ul><li>steroid or 5-aminosalicylic acid enemas administered </li></ul></ul></ul></ul>
  70. 71. Associated Carcinoma <ul><li>Most are adenocarcinomas of varying degrees of differentiation </li></ul><ul><li>Compared with carcinoma not associated with colitis: </li></ul><ul><ul><li>higher proportion of: </li></ul></ul><ul><ul><ul><li>poorly differentiated and mucinous carcinomas </li></ul></ul></ul><ul><ul><li>always present </li></ul></ul><ul><ul><li>usually in flat atrophic mucosa </li></ul></ul><ul><ul><li>distinguish from those due to regeneration atypia </li></ul></ul><ul><ul><li>should not be diagnosed in areas of active inflammation </li></ul></ul><ul><ul><li>evaluation difficult but successful in identifying those at high risk for colorectal carcinoma </li></ul></ul>
  71. 72. Fig. 9:  Adenocarcinoma with mucinous features arising in a colon affected by ulcerative colitis. This is a common tumor subtype in this particular setting. Fig. 10:  Dysplasia in ulcerative colitis. Indefinite for dysplasia. Fig. 11:  Dysplasia in ulcerative colitis. Low-grade dysplasia.
  72. 73. Fig. 12:  Dysplasia in ulcerative colitis. High-grade dysplasia. Fig. 13:  Dysplasia in ulcerative colitis. Dysplasia with papillary features.
  73. 74. Signs and Symptoms Diarrhea- frequent watery stools are the norm -stools are accompanied by thick blood (not bright red smears of blood, which usually occur from a bleeding hemorrhoid). -Mucus or pus also often passes with the stool. -Individual with ulcerative colitis will have stool of more normal consistency that contains pus or mucus.
  74. 75. <ul><li>Abdominal Pain </li></ul><ul><li>often crampy in nature and felt on the left side of the abdomen. This is because the rectum is above the anus moves to the left side, where it connects to the rest of the colon. </li></ul><ul><li>the pain and cramps subside immediately after a bowel movement. </li></ul><ul><li>Fever </li></ul><ul><li>Some individuals with ulcerative colitis suffer a high fever, especially during the acute phase of a flare-up . Others run a persistent, low-grade fever. </li></ul><ul><li>fever may be accompanied by irritability and fatigue. </li></ul><ul><li>Sometimes, the fever comes back each day, especially later in the day, then repeatedly breaks during sleep, causing night sweats. </li></ul><ul><li>Other symptoms may include fatigue, weight loss and loss of appetite . </li></ul>
  75. 76. Signs and Symptoms Unrelated To The GI Tract <ul><li>Reddening and inflammation of the eye (iritis) </li></ul><ul><li>Joint pains, usually in the large joints of the knees, ankles, elbows, wrists, and shoulders, which sometimes migrate from one joint to another (migrating arthralgia) </li></ul><ul><li>Skin lesions including tender red nodules on the shins or calves (erythma nodosum) </li></ul><ul><li>Sores inside the mouth (aphthous ulcers) </li></ul>
  76. 77. Complications <ul><li>Bleeding: Rectal bleeding and bloody diarrhea are two of the hallmark symptoms of ulcerative colitis. </li></ul><ul><li>Anemia: In ulcerative colitis, this is usually the result of chronic blood loss. To combat anemia, gastroenterologists often prescribe supplements, and recommend a diet rich in iron. </li></ul><ul><li>Malnutrition: Symptoms such as diarrhea and rectal bleeding can lead to a loss of fluids and nutrients. </li></ul><ul><li>Growth retardation: In children with ulcerative colitis, a combination of factors, including malnutrition and the use of corticosteroid treatment, may contribute to growth retardation. </li></ul>
  77. 78. <ul><li>Osteoporosis: Ulcerative colitis patients are at risk for low bone density, chiefly due to long-term use of some medications, such as steroids. </li></ul><ul><li>Venous thrombosis : most often in iliac vein </li></ul><ul><li>Strictures: Abnormal narrowing of the intestine. </li></ul><ul><li>Obstruction: Swelling and scarring obstructing the intestine. </li></ul><ul><li>Colon cancer: Ulcerative colitis patients have a higher risk of developing colon cancer. The risk increases when a greater proportion of the colon is affected, or if a patient has had ulcerative colitis for a prolonged period of time. Gastroenterologists may recommend that certain ulcerative colitis patients undergo periodic screening for colon cancer, based on disease duration. </li></ul>
  78. 79. <ul><li>Perforation: Extensive inflammation can lead to a tear in the intestinal wall, resulting in leakage of bowel contents outside the intestine. Categorized by sudden, severe abdominal pain, shock, and excessive abdominal tenderness. </li></ul><ul><li>Toxic megacolon: This serious complication may occur when inflammation spreads from the lining of the colon to involve the entire intestinal wall. Because this involvement temporarily stops the normal contractile movements of the intestine, the large intestine may greatly expand. </li></ul>
  79. 80. Fig. 6:  Ulcerative colitis. Case complicated with toxic megacolon. Fig. 7:  Ulcerative colitis complicated by toxic megacolon.
  81. 82. <ul><li>The diagnosis of IBD is based on a combination of examinations: </li></ul><ul><li>Non laboratory test </li></ul><ul><li>endoscopic (different types of scopes) </li></ul><ul><li>radiologic (x-rays) </li></ul><ul><li>Laboratory test </li></ul><ul><li>Routine test </li></ul><ul><li>Antibody test </li></ul>
  82. 83. Laboratory Tests <ul><li>There are two types of laboratory tests, which IS routine tests and antibody tests. </li></ul><ul><li>&quot;Routine&quot; Tests </li></ul><ul><li>• Stool culture to look for bacterial infection </li></ul><ul><li>• O&P (Ova and parasite) to detect parasites </li></ul><ul><li>• Clostridium difficile to detect toxin created by bacterial infection; may be seen following antibiotic therapy </li></ul><ul><li>• Fecal occult blood to look for blood in the stool </li></ul><ul><li>• Stool WBC to detect white blood cells in the stool </li></ul><ul><li>• Celiac Disease tests </li></ul>
  83. 84. Tests that are not specific for IBD but done to detect and evaluate the inflammation and anemia associated with IBD include: <ul><li>• ESR (erythrocyte sedimentation rate) to detect inflammation </li></ul><ul><li>• CRP (C-reactive protein) to look for inflammation </li></ul><ul><li>Calprotectin is a protein associated with inflammation. Its use as an inflammatory marker to help diagnose and monitor IBD when measured in stool (fecal) samples is gaining attention. It may prove to be a useful test in predicting relapses in IBD patients. </li></ul><ul><li>• CBC (complete blood count) to check for anemia </li></ul>
  84. 85. Antibody Tests <ul><li>The antibodies are named &quot;perinuclear anti-neutrophil antibody&quot; (pANCA) </li></ul><ul><li>&quot;anti-Saccharomyces cervisiae antibody&quot; (ASCA). </li></ul><ul><li>Many patients with ulcerative colitis have the pANCA antibody in their blood, but not the ASCA antibody. For many Crohn's patients, the opposite is true: the ASCA antibody is present, while the pANCA is not. </li></ul><ul><li>Unfortunately, some patients have neither antibody in their blood, and some Crohn's patients may have only the &quot;ulcerative colitis&quot; pANCA antibody in their blood! Nevertheless, sometimes these blood tests help your doctor determine which condition is more likely, which may help in making decisions regarding medications or surgery. </li></ul><ul><li>Anti-CBir1 (Clostridium species antibodies), found to be associated with about 50% of Crohn’s disease cases. </li></ul><ul><li>Anti-Omp C (Escherichia coli antibodies), associated with rapidly progressing Crohn’s disease. </li></ul><ul><li>Anti-I-2 (Pseudomonas fluorescens antibodies </li></ul>
  85. 86. Non-Laboratory Tests <ul><li>Endoscopy </li></ul><ul><li>Endoscopy has four main procedures, or different types of &quot;scopes&quot;, that are used to evaluate IBD. All use a thin, flexible tube with a lighted camera inside the tip, which allows your doctor to look directly at the lining of the gastrointestinal (GI) tract. </li></ul><ul><li>Types of Endoscopy </li></ul><ul><li>Sigmoidoscopy </li></ul><ul><li>looks at the lower one-third of the colon. This makes it is a useful test when your physician wants to confirm the presence of inflammation or a source of bleeding (such as hemorrhoids) within the reach of the scope. </li></ul><ul><li>helps rule out infectious causes of inflammation, such as disease caused by bacteria, which may mimic IBD. It is also useful in evaluating symptoms that do not respond to your current treatment or that return despite treatment. </li></ul>
  86. 87. <ul><li>Colonoscopy </li></ul><ul><li>can assess the complete extent of colitis. </li></ul><ul><li>It is also useful for evaluating and taking biopsies of the distal small intestine (terminal ileum), which is important in the evaluation of Crohn's diseaseand chronic colitis. </li></ul><ul><li>When colonoscopy is performed to look for dysplasia, multiple biopsies are taken throughout the entire colon and rectum. Surveillance refers to routine examinations of the colon to minimize the risk of cancer by checking for dysplasia and monitoring any changes </li></ul>
  87. 88. <ul><li>EGD(esophago-gastro-duodenoscopy) </li></ul><ul><li>EGD is a common procedure that is used to evaluate a wide variety of symptoms, such as abdominal pain, nausea, vomiting, and painful swallowing. Occasionally a longer EGD, called an enteroscope. </li></ul>
  88. 89. <ul><li>Capsule &quot;Minicamera&quot; Endoscopy </li></ul><ul><li>It is designed to show images of sections of the small intestine that are beyond the reach of an EGD. This test is to determine obscure gastrointestinal bleeding. It takes approximately two hours for your doctor to review the images. The capsule is excreted in the stool normally and effortlessly. For patients with Crohn's disease, patients must be examined carefully to determine that there are no strictures or bowel obstructions before the capsule can be used. </li></ul>
  89. 90. <ul><li>ERCP (Endoscopic retrograde cholangiopancreatography): </li></ul><ul><li>A small percentage of patients with IBD also may have a liver disease called &quot;primary sclerosing cholangitis,&quot; or PSC. A doctor may suspect PSC if repeatedly abnormal blood test results reflect the activity of enzymes in the liver. ERCP is a method that combines X-ray and endoscopy to look at your bile ducts and pancreatic ducts. As in an EGD, a tube is passed through your stomach and into your small bowel. The papilla, a small bump with a tiny opening in your duodenum, leads to your biliary and pancreatic ducts. A small catheter is introduced through the papilla into either your bile ducts or your pancreatic duct and contrast dye is injected. </li></ul>
  90. 91. <ul><li>EUS (endoscopicultrasound ) </li></ul><ul><li>is a relatively new technique that uses an ultrasound probe attached to an endoscope to obtain deep images of the gut below the surface. In IBD, this is most often used to look at fistulas in the rectal area. EUS can determine the depth and extent of the fistula and biopsies can be taken if needed. </li></ul>
  91. 92. Radiology Tests <ul><li>Plain X-ray </li></ul><ul><li>Plain X-rays (without contrast) are a quick, inexpensive, and effective way of detecting blockage in the small or large intestine. Patients with Crohn's disease,have inflammation of the small bowel that narrows the intestine and prevents the easy passage of stool and air. The large bowel can also become blocked and dilated. People with ulcerative colitis develop widening of the large bowel called toxic megacolon. </li></ul>
  92. 93. <ul><li>X-rays With Contrast </li></ul><ul><li>To look for Narrowing of the bowel (stricture) and an abnormal channel between the bowel and another organ (fistula) are two conditions more easily diagnosed with a contrast X-ray. </li></ul><ul><li>The contrast used for these tests is barium. It is a thick, chalky liquid that can be given by mouth or via the rectum. </li></ul><ul><li>* 2 types of contrast X-rays of the small intestine: </li></ul><ul><li>i)small bowel follow through and enteroclysis. </li></ul><ul><li>ii)large bowel X-ray is called a barium enema. </li></ul>
  93. 94. <ul><li>CAT Scan </li></ul><ul><li>MRI </li></ul><ul><li>Ultrasound </li></ul><ul><li>White Blood Cell Scan </li></ul><ul><li>Leukocyte scintigraphy or &quot;tagged white blood cell scan&quot; detects white blood cell accumulation in inflamed tissue. </li></ul><ul><li>Leukocyte scintigraphy has been used to detect the location of bowel inflammation and to evaluate treatment response in IBD. It is not useful in defining anatomic details or looking at inflammation in the rectum. It is a relatively safe test and entails less radiation exposure than contrast X-ray or CT scan. </li></ul>
  94. 95. Management <ul><li>Medical management of ulcerative colitis (UC) </li></ul><ul><li>UC should be treated with an aminosalicylate </li></ul><ul><li>Proctitis </li></ul><ul><li>First-line treatment </li></ul><ul><li>Oral aminosalicylates plus a local rectal steroid preparation (10% hydrocortisone foam; prednisolone 20 mg enemas or foam) </li></ul><ul><li>Resistant to treatment </li></ul><ul><li>Mesalazine (Anti-inflammatory) enemas and budesonide (steroid) enemas. </li></ul><ul><li>Oral corticosteroids 20-40mg/day alone or in combination with azathioprine 2-2.5mg/kg/d PO (Anti-immune)are used </li></ul>
  95. 96. Medical management of UC <ul><li>Mild <4 motion </li></ul><ul><li>Pred 20-40mg/d PO + Mesalazine (400-500mg up to 1g/6hr) or </li></ul><ul><li>Steroid foam (twice daily)PR or pred 20 mg retention enema </li></ul><ul><li>Moderate 4-6motion </li></ul><ul><li>Oral pred 20-40 /d for 1wk and tail off+5ASA +BD steriod enema </li></ul><ul><li>Severe(systemic illness) </li></ul><ul><li>Admit-nothing by mouth </li></ul><ul><li>Hydration </li></ul><ul><li>Hydrocortisone 100mg/6hr IV </li></ul><ul><li>Rectal steriod – 100mg in 100 ml 0.9%saline/12 hr PR </li></ul><ul><li>Pred PO 40mg/24hr +5ASA(sulfaslazine 500mg/6hr for remission) </li></ul>
  96. 97. Medical management of UC <ul><li>Mild (symtomatic ) </li></ul><ul><li>Pred 30mg/d PO 1wk tail off </li></ul><ul><li>Severe </li></ul><ul><li>Admit IV steroid100 mg/6h /IV , hydration (0.9%saline +2L glucose +20mmol K+/L ) </li></ul><ul><li>Metro 400mg/8hr/PO or 500mg/8H IV </li></ul><ul><li>After 5day- oral pred 40mg/d) </li></ul>
  97. 98. Management <ul><li>Left-sided proctocolitis </li></ul><ul><li>Oral aminosalicylates plus local rectal steroid preparations(hydrocortisone 100mg in 100ml 0.9% saline/12 hr PR) may be effective but in moderate to severe attacks oral prednisolone will be required. </li></ul><ul><li>If patients do not respond within 2 weeks they should be admitted to hospital. </li></ul>
  98. 99. Management <ul><li>Total colitis (moderate to severe attacks) </li></ul><ul><li>Admitted to hospital ( hydrocortisone 100 mg i.v. 6-hourly with oral aminosalicylates) </li></ul><ul><li>Full supportive therapy (Fluids, nutritional support via the enteral (not parenteral) route. </li></ul><ul><li>Clinical status monitored - fever, tachycardia, abdominal signs) and daily FBC, ESR, CRP, electrolytes and urea, LFT , serum albumin, abdominal X-ray and stool examination </li></ul><ul><li>Success or failure of medical treatment </li></ul>
  99. 100. Drugs for IBD <ul><li>1.Aminosalicylates—anti-inflammatory agents </li></ul><ul><li>2.Corticosteroids (steroids):— Usually provide significant suppression of inflammation and rapid relief of symptoms. </li></ul><ul><li>3.Immune modifiers –Thiopurines , Methotrexate </li></ul><ul><li>4.Anti-tumor necrosis factor (anti-TNF) agents (but not for “first-line” therapy): — Infliximab only proven therapy in the treatment of fistulas, , adalimumab, and certolizumab </li></ul><ul><li>5. Antibiotics: </li></ul><ul><li>Metronidazole and ciprofloxacin are the most commonly used antibiotics in CD. </li></ul><ul><li>Treatment of CD complications (perianal disease, fistulas, inflammatory mass, bacterial overgrowth in setting of strictures). </li></ul><ul><li>6. Probiotics: — IBD may be caused or aggravated by alterations in the gut flora. </li></ul><ul><li>7. Symptomatic therapy and supplements </li></ul><ul><li>8. Antidiarrheals such as loperamide (Imodium) </li></ul><ul><li>9. Nutritional supplementation for those with malnutrition </li></ul><ul><li>10.Routine vitamin D and calcium supplementation for steroid users. </li></ul><ul><li>11.Routine multivitamin supplementation for all. </li></ul><ul><li>12.chronic iron-deficiency anemia, use parenteral iron (either as weekly intramuscular shots or dosing with intravenous iron) </li></ul>
  100. 101. Management <ul><li>Not responding to treatment </li></ul><ul><li>A persistent fever, tachycardia, falling Hb, rising white cell count, falling potassium, falling albumin and persistently raised stool weights (> 500 g/day) with loose blood-stained stool) </li></ul><ul><li>SURGERY may be indicated </li></ul><ul><li>Surgical management of ulcerative colitis </li></ul><ul><li>While the treatment of UC remains primarily medical </li></ul><ul><li>Surgery continues to have a central role because it may be lifesaving, is curative and eliminates the long-term risk of cancer </li></ul>
  101. 102. Principles of Surgery <ul><li>For UC, surgery should be advised for disease not responding to intensive medical therapy </li></ul><ul><li>For CD, surgery should only be undertaken for symptomatic rather than asymptomatic </li></ul><ul><li>Patients requiring surgery for IBD are best managed under the joint care of a surgeon and a gastroenterologist with an interest in IBD </li></ul>
  102. 103. <ul><li>The procedure of choice in acute fulminant UC or CD is a subtotal colectomy leaving a long rectal stump, either: </li></ul><ul><li>incorporated into the lower end of the abdominal wound , or </li></ul><ul><li>exteriorised as a mucus fistula </li></ul><ul><li>This is to facilitate later rectal excision and minimise the risk of intraperitoneal dehiscence ( grade B ). </li></ul>
  103. 104. <ul><li>Patients requiring elective surgery for UC should be counselled regarding all surgical options, including ileoanal pouch where appropriate ( grade C ). </li></ul><ul><li>Resections in CD should be limited to macroscopic disease ( grade A ). </li></ul><ul><li>Primary anastomosis should not be performed in the presence of sepsis and malnutrition ( grade B ). </li></ul><ul><li>Anal and perianal CD should be treated surgically only when symptomatic ( grade B ). </li></ul><ul><li>Procedures for perianal CD should usually be conservative and in conjunction with medical treatment, particularly aiming at drainage of sepsis. </li></ul><ul><li>Repair of fistulas may be appropriate in selected cases with absent or minimal rectal disease ( grade B ). </li></ul>
  104. 105. Grading of recommendations <ul><li>The guidelines conform to the North of England evidence based guidelines development project. The grading of each recommendation is dependent on the category of evidence supporting it: </li></ul><ul><li>Grade A —requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence categories Ia and Ib). </li></ul><ul><li>Grade B —requires the availability of clinical studies without randomisation on the topic of consideration (evidence categories IIa, IIb, and III). </li></ul><ul><li>Grade C —requires evidence from expert committee reports or opinions or clinical experience of respected authorities, in the absence of directly applicable clinical studies of good quality (evidence category IV). </li></ul>