IBD.pdf

Inflammatory Bowel Disease (IBD) 9 & 10 ILOs At the end of this session, the student will be able to:  Define the IBD.  Highlight the epidemiology of IBD.  Explain the etiopathogenesis of IBD  Discuss the clinical manifestations of Ulcerative Colitis (UC) whe...

Inflammatory Bowel Disease (IBD) 9 & 10 ILOs At the end of this session, the student will be able to:  Define the IBD.  Highlight the epidemiology of IBD.  Explain the etiopathogenesis of IBD  Discuss the clinical manifestations of Ulcerative Colitis (UC) whether intestinal or extraintestinal.  Discuss the clinical manifestations of Crohn’s Disease (CD) and its types.  Appraise the extraintestinal manifestations of IBD.  Highlight the diagnosis of UC & CD Inflammatory Bowel Disease (IBD) IBD is a chronic inflammatory condition of the intestines that is marked by remission and relapses and distills clinically into one of two major subtypes of disease: Ulcerative Colitis (UC) and Crohn’s Disease (CD). Both diseases have a general commonality in their pathogenesis and are derived from a dysregulated mucosal immune response to antigenic components of the normal commensal microbiota that reside within the intestine. Epidemiology: The prevalence and incidence of IBD has geographic and socioeconomic variations. The incidence of ulcerative colitis in North America is estimated to be 8–15 per 100,000 persons, with a prevalence of 170–230 per 100,000. Crohn disease has an estimated incidence of 5–15 per 100,000 and prevalence of 140–200 per 100,000. An increased incidence and prevalence of both forms of IBD is found in developed nations, northern locale (at least within the northern hemisphere), and urban environments; among Caucasians; and among persons of Jewish ethnicity. In industrialized countries, the incidence of Crohn disease has risen significantly over the past half century, Page 1 of 20 whereas that of ulcerative colitis has remained relatively steady. In developing countries, the incidence of both forms of IBD has dramatically risen. IBD typically presents at a relatively young age, often in adolescence. The median age of diagnosis for Crohn disease and ulcerative colitis is the third and fourth decades of life, respectively. Studies have suggested a second, smaller peak in incidence of IBD in the sixth and seventh decades, although this association is clearer for ulcerative colitis than for Crohn’s disease. As regards the gender, both males and females are equally affected. Etiology: The cause of IBD remains elusive, although interplay of genetic, microbial, and immunologic factors clearly exists.  Genetic factors: susceptibility genes have been identified, including NOD2/CARD15 on chromosome 16 and IL23R on chromosome 1, in Crohn disease. Both play integral roles in immune regulation within the gut. At the same time, mutations in these genes are present in only a minority of Crohn disease cases.  Microbial and environmental factors: Animal studies have demonstrated that the presence of commensal gut bacteria is necessary for IBD to occur. In theory, the subsequent enteritis or colitis results from a dysregulated or inappropriate immune response to flora tolerated by healthy individuals. Other environmental factors appear important as well. Cigarette smoking increases the risk for Crohn disease but is protective for ulcerative colitis. Both oral contraceptive and nonsteroidal anti- inflammatory medications have been implicated as risk factors for IBD. Appendectomy may protect against the UC.  Immune factors: Gut-associated lymphoid tissues (GALT) are characterized by a unique structure, physiologic inflammation, a tendency to suppress immune responses (oral tolerance), and production of secretory immunoglobulins. The immune response has two major arms: innate (rapid, hard-wired) and adaptive (delayed in onset with memory). IBD is ultimately caused by overproduction of proinflammatory mediators relative to anti-inflammatory mediators, both of which are derived from cells associated with adaptive immunity (T helper [Th] cells) and innate immunity (macrophages and dendritic cells) that excessively infiltrate the intestinal tissues. Although Crohn’s disease (CD) may preferentially exhibit overactivity of Th1 and Th17 cells, and ulcerative colitis (UC) may exhibit overactivity of Th2 cells, there is significant overlap in the immunopathogenesis of these disorders. Excess production of cytokines derived from innate immune Page 2 of 20 pathways (tumor necrosis factor [TNF] and interleukin-6 [IL-6]) occurs in both CD and UC. Crohn’s Disease: Crohn’s is the name of the doctor who first described the disease in US in 1932. The inflammation in Crohn disease is typically transmural. This frequently leads to complications from perforating disease or from progressive fibrosis and stricturing. Crohn’s disease can thus be thought of as fitting one of three phenotypes: inflammatory, stricturing, or perforating disease (the latter including abscesses and fistulae). Disease behavior is not necessarily constant in an individual patient. Indeed, inflammatory disease frequently progresses to penetrating disease, and then to fibrosis and stricturing. Crohn’s disease may affect any part of the alimentary canal, and may do so in a nonconfluent (so-called skip lesion) pattern. Nearly half of all patients with Crohn disease have inflammation localized to the terminal ileum and cecum (Table 1). Isolated small bowel or colonic involvement is also common. Crohn’s disease of the esophagus, stomach, or duodenum is rare, and virtually unheard of in the absence of small bowel or colonic disease. Perianal disease, including abscesses and fistulae, is commonly encountered, particularly in conjunction with terminal ileal disease. Symptoms and signs The onset of symptoms in Crohn’s disease is typically insidious, and the subsequent clinical course is highly variable. For the majority of patients, the clinical course is characterized by recurring episodes of symptomatic disease interspersed with periods of remission. Abdominal pain and diarrhea are the most typical symptoms. Unlike ulcerative colitis, the diarrhea in Crohn’s disease is often nonbloody. Fever and weight loss are common. As a general rule, the location and phenotype of disease (inflammatory, stricturing, or perforating), along with the severity of inflammation, dictate a patient’s symptoms and signs. Pain and drainage of purulent or fecal material are characteristic of perianal fistulae. Fistulae from the gut may cause a variety of symptoms, depending on the sites of origin and other organ(s) involved: gut—diarrhea, weight loss; skin—drainage; vagina—drainage; bladder—pneumaturia. Stricturing disease causes obstructive symptoms of pain, abdominal distention, nausea, and vomiting. Page 3 of 20 Signs of Crohn disease include abdominal tenderness, most classically in the right lower quadrant. An abdominal mass may be palpable. Temporal wasting and cachexia indicate significant malnutrition. Typical symptoms of small bowel obstruction (distention, tympany, high-pitched bowel sounds) may be present in stenosing disease. Perianal and cutaneous fistulae are readily identified on a careful perineal and skin examination. Laboratory findings: No single laboratory test is diagnostic or specific for Crohn disease.  Patients are typically at least mildly anemic, often with iron deficiency. Leukocytosis and thrombocytosis are common and typically reflect systemic inflammation.  Serum albumin may be low in the case of protein-losing enterocolitis or in malnutrition.  Malabsorption due to inflammation, bacterial overgrowth, or surgical resection may lead to diminished levels of various minerals (serum calcium and magnesium) and vitamins (B12, D, and folate).  C-reactive protein (CRP)—and, to a lesser extent, erythrocyte sedimentation rate (ESR)—are nonspecific markers of inflammation that are frequently elevated in Crohn disease.  Stool examination may reveal excess fat, indicative of malabsorption, or fecal leukocytes, indicative of gut inflammation. Stool studies should be negative for infectious pathogens, including standard bacterial pathogens, Clostridium difficile, and ova and parasites.  Stool inflammatory markers like fecal lactoferrin and calprotectin, are available that can help distinguish IBD from irritable bowel syndrome (IBS) (conditions that often have overlapping symptoms), potentially gauge disease activity, predict flare, and monitor and/or assess response to treatment.  Various serologic markers have been linked with Crohn disease, including antibodies to the yeast Saccharomyces cerevisiae (ASCA), to bacterial proteins Omp-C and I2, and to clostridial flagellin, CBir-1. Antineutrophil cytoplasmic antibodies (ANCA, P-subtype) are associated with both ulcerative colitis and Crohn colitis. As individual tests, these markers have limited diagnostic accuracy, but in select situations may be helpful in distinguishing Crohn disease from other inflammatory conditions. Page 4 of 20 Imaging studies:  Standard abdominal plain films are useful for detecting obstructive disease and megacolon, but otherwise have a limited role in imaging Crohn disease.  Computed tomography (CT) of the abdomen and pelvis has revolutionized the imaging of Crohn disease by allowing imaging of the bowel wall itself, as well as extraluminal disease such as abscesses or inflammatory masses. Common abnormalities of the gut include thickening and excessive mesenteric fat proliferation (so-called creeping fat). CT enterography, which uses a special low-density oral contrast, combines the advantages of CT and small bowel series by allowing detailed pictures of the small bowel mucosa.  Magnetic resonance enterography (MRE) has been increasingly used. Studies have shown MRE to have better detection of mild disease than CT enterography (CTE) and slightly improved detection of wall thickening and enhancement. No significant difference was seen for moderate to severe disease. Figure 1  MRI pelvis to localize perianal fistulae and abscesses. Figure 2  US intestines is safe and new modality which can visualize the intestines, and colon without hazards of irradiation or the contrast. Endoscopy:  Colonscopy (figure 3 and 4) remains a mainstay in the assessment of Crohn disease, as it allows direct visualization of the bowel mucosa and sampling of tissue. findings include ulcerations, erythema, granularity, and strictures. Pseudopolyps may be present. Ileal ulceration and skip lesions help distinguish Crohn disease from ulcerative colitis. The rectum is often spared. Fistulae are often difficult to locate endoscopically and are best seen by contrast studies or MRI.  Enteroscopy visualizes parts of small intestines.  Capsule endoscopy can visualize the small intestine provided there was no stricture otherwise retention of the capsule can occur and require surgical exploration. Complications of CD:  Crohn disease frequently causes complications from penetrating and stenosing disease, including perforation, abscess, fistulae, and obstruction. Page 5 of 20   Active small bowel disease or extensive small bowel resection may lead to complications from malabsorption, the severity of which depends on the location and extent of nonfunctioning (or surgically excised) bowel.  Deficiencies in iron, folate, vitamin B12, and fat-soluble vitamins (A, D, E, and K) are common, with resulting complications including anemia and osteoporosis. Because Crohn disease has a predilection for the ileum, bile salt reabsorption is frequently compromised. Resection of 50–100 cm of ileum typically causes bile salts to spill into the colon, resulting in a bile salt– induced diarrhea (responsive to bile acid sequestrants). If more than 100 cm of ileum is resected or diseased, reabsorption of bile salts may be so impaired that the total pool is depleted, causing fat maldigestion and steatorrhea.  Extensive small bowel disease or resection can also lead to short gut syndrome, with protein calorie and micronutrient deficiency and dependence on parenteral nutrition.  Small bowel bacterial overgrowth frequently complicates Crohn disease, particularly in the setting of stricturing disease or after resection of the ileocecal valve.  Malabsorption of fatty acids predisposes patients with Crohn disease to renal calculi. Calcium readily binds unabsorbed fatty acids, allowing oxalate to be taken up by the bowel in greater quantity. Subsequent renal excretion of this excess oxalate promotes the precipitation of calcium oxalate calculi. Ulcerative Colitis: Inflammation in ulcerative colitis is limited to the mucosal layer of the colon. The rectum is virtually always involved, with inflammation extending proximally in a confluent fashion. The extent of proximal involvement is variable. A significant proportion of patients have disease confined to the rectum (ulcerative proctitis). Roughly one-third of patients have proctosigmoiditis, and the majority of patients have gross colitis only distal to the splenic flexure. Approximately one-third of patients have disease that extends proximal to the splenic flexure (extensive colitis), often involving the entire colon (pancolitis). Cecal patch can be found especially in children with peri appendiceal involvement. Backwash ileitis can occur in UC especially in extensive colitis. The previous conditions make the differentiation between UC and CD difficult. Also skip lesions can be found in patients with UC under treatment. Page 6 of 20 Unlike Crohn disease, ulcerative colitis is frequently acute or subacute in onset. Like Crohn disease, the subsequent clinical course is one of recurring episodes symptomatic disease interspersed with episodes of relative (or complete) quiescence. Symptoms and signs As with Crohn disease, the symptoms of ulcerative colitis depend on the extent and severity of inflammation. Overt rectal bleeding and tenesmus are virtually universally present and may be the only symptoms in patients with proctitis alone. When the proximal colon is involved, diarrhea and abdominal pain are more frequent complaints. Nausea and weight loss portend more severe disease. Severe abdominal pain or fever suggests fulminant colitis or toxic megacolon. Signs of ulcerative colitis include mild abdominal tenderness, often most localized in the hypogastrium or left lower quadrant. Digital rectal examination may disclose visible red blood. As with Crohn disease, signs of malnutrition may be evident. Severe tenderness, fever, or tachycardia heralds fulminant disease. Laboratory findings:  Anemia and low iron, leukocytosis, thrombocytosis can be found. hypoalbuminemia if the disease is severe and extensive. CRP and ESR are elevated but they are non-specific inflammatory markers.  Stool studies should be sent and found negative for typical bacterial pathogens, C difficile, and ova and parasites. Common positive findings in ulcerative colitis include fecal leukocytes and fecal calprotectin.  Serologic markers have also been studied for ulcerative colitis. P-ANCA is the most commonly associated marker. However, it is also present in Crohn colitis, which limits its ability to distinguish the two conditions. As with markers in Crohn disease, P-ANCA may be helpful in predicting disease activity. Studies have suggested that P-ANCA-associated ulcerative colitis is more likely to be medically refractory, require early surgery, and result in chronic pouchitis in patients who have undergone ileal pouch anal anastomosis (IPAA). Imaging studies:  Plain films of the abdomen are useful predominantly in patients with symptoms of severe or fulminant colitis. So-called thumbprinting or thickening of the colon wall indicates severe colitis with bowel wall edema. With toxic megacolon, the bowel is dilated with loss of haustral markings. Intestinal pneumatosis is a late Page 7 of 20 finding and signals bowel ischemia and infarction. Obstructive findings are less common in ulcerative colitis than in Crohn disease and usually suggest malignancy. Figure 7  Barium enema is less commonly used since the advent of flexible sigmoidoscopy and colonoscopy. Nonetheless, it can be useful for detecting active ulcerative disease, polyps, or masses. In ulcerative colitis, the colon typically appears granular and shortened, perhaps as a consequence of chronic inflammation or fibrosis. Pouchography (contrast study of the pouch) in patients who have undergone IPAA permits assessment of diseases related to this operation, including leaks, pouchitis, fistulae, or strictures.  CT of the abdomen typically reveals colonic wall thickening, as with other forms of colitis. Figure 8  Colonoscopy allows assessment of the extent of disease and severity of involvement. Classic findings include confluent inflammation extending proximally from the anal verge, with mucosal erythema, edema, and granularity and loss of normal vasculature. The transition between the involved part and the normal part is abrupt. With more severe disease, the mucosa becomes overtly hemorrhagic, with ulcerations and a purulent exudate. So-called backwash ileitis, characterized by mild terminal ileal erythema, is seen in patients who have pancolitis. Pseudopolyps are commonly encountered in patients with long-standing disease. These are polypoid nondysplastic colonic lesions of hypertrophied tissue, often with surrounding atrophic mucosa. They are thought to represent the sequelae of chronic recurrent inflammation and healing and harbor no malignant potential. Dysplastic or frankly malignant polyps or mass lesions are also encountered at higher rates in patients with ulcerative colitis. Figure 9  Histopathology examination of biopsies are important for diagnosis, assessment of disease activity, and detection of early dysplasia and neoplasia. The biopsies should be two biopsies from each 5 segments of the colon including the terminal ileum and rectum. The histopathological findings at early stage include basal plasmacytosis, with more severe disease there is Widespread mucosal or crypt architectural distortion, mucosal atrophy, and an irregular or villous mucosal surface, with active inflammation causing cryptitis and crypt abscesses. Figure 5 Histological mucosal healing is characterized by the resolution of crypt architectural distortion and inflammatory infiltrate. However, the mucosa can still show some features of sustained damage, such as decreased crypt density with branching and atrophy of crypts. Granulomas (pathognomonic in CD but its absence doesn’t exclude the diagnosis). Figure 10 Page 8 of 20 Extraintestinal manifestations of IBD: Table 2 Crohn disease and ulcerative colitis may be associated in 50% of patients with a number of extraintestinal manifestations, including oral ulcers, oligoarticular or polyarticular nondeforming peripheral arthritis, spondylitis or sacroiliitis, episcleritis or uveitis, erythema nodosum, pyoderma gangrenosum, hepatitis and sclerosing cholangitis, and thromboembolic events. Complications:  Life threatening hemorrhage.  Acute severe ulcerative colitis which is life threatening and might require surgical resection of the colon if more complications with colonic perforation or toxic megacolon.  Colorectal cancer: is the most feared long-term complication for ulcerative colitis. Risk factors include duration and extent of disease, severity of inflammation, family history of CRC, and concomitant primary sclerosing cholangitis (PSC). Early age of onset has been suggested to be a risk factor. The excess risk of CRC appears after 8–10 years of disease. Hence, a screening colonoscopy is recommended after 8 years for patients with extensive colitis, with surveillance examinations every 1–2 years.  Pouchitis is a condition unique to patients who have undergone an IPAA. Diagnostic Considerations  No single symptom, physical finding, or test result can diagnose. The diagnosis of both Crohn disease and ulcerative colitis is a clinical one, based on compatible patient history; physical examination; and laboratory, radiographic, endoscopic, and histologic findings.  For both the initial diagnosis and subsequent flares, other conditions that mimic IBD should be excluded. Of particular importance is the exclusion of infectious pathogens, as the treatment of active IBD frequently involves immunosuppressive medications. Differential diagnosis: Table 5 1. UC versus CD: Indeterminant colitis 2. IBS 3. Infectious colitis Page 9 of 20  4. Condition mimic IBD e.g., Diverticulitis, Appendicitis, Lymphoma, Malignancy 5. Non-infectious colitis: Collagenous colitis and lymphocytic colitis (Microscopic colitis). Radiation proctocolitis. Ischemic colitis. NSAID-induced colitis. Other: Diversion colitis, Colitis chronic granulomatous colitis (CGD), GVHD association Amyloid colitis. Table 1: classifications used for Crohn’s disease: Page 10 of 20 Figure 1: MR images of visceral adipose tissue as seen in Crohn’s disease (B) compared with healthy volunteer of same body mass index (A). Page 11 of 20 Figure 2: MR images showing a perianal fistula (long white arrows), before (A, B) and after 3 months of biological therapy (C, D). Page 12 of 20 Figure 3: Colonoscopy in patient with CD showed cobble stone appearance. Figure: 4 Page 13 of 20 Figure 5: Microscopic findings in Crohn’s disease. The inflammatory infiltrate in Crohn’s disease is patchy, often transmural and can lead to fissuring ulcers (marked by arrow). H&E), ×200 (A). Granulomas seen in relation to ruptured crypts are termed cryptolytic granulomas (marked by arrows) and are not specific for a diagnosis of CD. granulomas is a hallmark of Crohn’s disease. They can be vaguely defined and difficult to detect (marked Histiocytic non caseating by arrow). Pyloric gland metaplasia (marked by “*”) in the terminal ileum is a typical sign of long- standing chronic inflammation in Crohn’s disease. Page 14 of 20 Table 2: Common extraintestinal manifestations of inflammatory bowel disease. Page 15 of 20 Table 3: Montreal classification of UC: Table 4: Mayo score for assessment of UC activity Page 16 of 20 Figure: 6 Page 17 of 20 Table 5: Differential diagnosis of IBD: Figure 7: Abdominal X ray in patient with Acute severe UC with dilated colon and thumbprinting sign of severe inflammation: Page 18 of 20 Figure 8: CT (a) Normal colon with wall thickness less than 3 mm (green arrow). (b) Colitis of the cecum with wall thickening measured as 10.6 mm (red arrows). (c) Colitis of the ascending with accordion sign (red arrows). Figure 9: Colonscopic findings in patient with severe UC with pseudopolyps: Page 19 of 20 Figure 10: Histopathological findings in patients with UC: Page 20 of 20