Intestine 5 and 6-2.pdf

Department of Anatomical Pathology National Health Laboratory Service & Nelson R Mandela School of Medicine MBChB Year 2: Theme 2.4. – GIT / Hepatobiliary System Topic: Intestine 5 & 6 – Inflammato...

Department of Anatomical Pathology National Health Laboratory Service & Nelson R Mandela School of Medicine MBChB Year 2: Theme 2.4. – GIT / Hepatobiliary System Topic: Intestine 5 & 6 – Inflammatory Bowel Disease Inflammatory bowel disease - Inflammatory bowel disease (IBD)is a chronic condition resulting from _________________ immune responses to normal gut flora - It comprises 2 disorders 1. Ulcerative colitis – severe ulcerating inflammatory disease limited to the colon and rectum, extending into the mucosa and submucosa 2. Crohn disease (CD) – regional enteritis (frequent ileal involvement) may involve any area of the gastrointestinal tract and is typically transmural Epidemiology - IBD is commoner in _________________ - Presents during adolescence and in the early twenties - It is more common in developed countries consistent with the hygiene hypothesis (reduced frequency of enteric infections results in inadequate development of mucosal immune regulation) Pathogenesis - IBD is an idiopathic disorder - It results from a combination of 1. Defects in host interactions with gastrointestinal flora 2. Intestinal epithelial __________________ 3. Aberrant mucosal immune responses - Transepithelial flux of microbes activates innate and adaptive immune responses - In a susceptible host, subsequent TNF release and other inflammatory signals increase the permeability of ___________________ - These events establish a self-amplifying cycle of microbial influx and host immune responses that culminate in IBD  Genetics - Risk of disease is increased when there is an affected family member - Concordance of monozygotic twins is 50% for CD and 16% for UC - ______________ (nucleotide oligomerisation binding domain 2) polymorphisms are linked to CD - NOD2 regulates immune responses to prevent excessive activation by luminal microbes - Additional genes (ATG16L1 and IRGM) are also related to microbial recognition and/or regulating subsequent immune responses - None of these genes are associated with UC  Mucosal immune responses - In CD, __________________ are polarized to produce TH1 cytokines - TH17 cells may also be contributory  2 - Polymorphisms in the IL-23 receptor (regulating TH17 cell development) may be protective - In UC, helper T cells tend to be polarized to produce TH2 cytokines - Polymorphisms near the IL-10 gene have been linked to UC  Epithelial defects - Barrier dysfunction, including defects in epithelial tight junctions, transporter genes and polymorphisms in extracellular matrix proteins or metalloproteinases are associated with IBD  Microbiota - Composition of gastrointestinal flora and the organisms in the intestinal mucus affect innate and adaptive immune responses - _________________ can be helpful in managing IBD Crohn disease Morphology - Occurs in any area of the gastrointestinal tract - The common sites of involvement are the __________________, ileoceacal valve and the cecum - CD involves the ________________ alone in 40% of cases and the small intestine and colon in 30%, the remainder only have colonic involvement Gross features - Skip lesions Separate, sharply delineated disease areas with granular and inflamed serosa and adherent mesenteric creeping fat The bowel wall is thick and rubbery and stricture Aphthous ulcers Cobblestone appearance Sparing of interspersed mucosa gives cobblestone appearance with diseased tissue depressed relative to normal mucosa ________________and fistula tracts are common Microscopic features - Mucosal inflammation and ulceration with intraepithelial neutrophils and _________________(clusters of neutrophils in a crypt) - Chronic mucosal damage with villous blunting, atrophy, pseudopyloric or Paneth cell metaplasia and distortion of mucosal architecture - Transmural inflammation with lymphoid aggregates in submucosa, muscle wall and subserosal fat - _______________________ occur throughout the gut even in uninvolved segments (35% of patients). Granulomas may also be present in mesenteric lymph nodes. Cutaneous granulomas form nodules referred to as metastatic CD. The absence of granulomas does not preclude a diagnosis of CD Clinical features  3 - Patients present with intermittent attacks of _______________, fever and abdominal pain - Asymptomatic periods can last for weeks to months - Depending on the segment affected, extensive CD can lead to _______________ and malnutrition, loss of albumin (protein losing enteropathy), iron deficiency anaemia and/or B12 deficiency - Fibrotic strictures or fistulas to adjacent viscera, abdominal and perineal skin, bladder or vagina typically require surgical resection Disease often recurs at the anastomosis with 40% of patients requiring additional surgery - Extraintestinal manifestations include uveitis, ___________________, sacroiliitis, ankylosing spondylitis, erythema nodosum and clubbing - There is increased risk of colonic ___________________ in patients with long standing colon involvement Ulcerative colitis Morphology - UC is a disease of ________________ with no skip lesions involving the rectum and extending proximally in retrograde fashion to involve the entire colon (______________) - The distal ileum may also show some inflammation (backwash ileitis) Gross features - Mucosa is reddened, granular and friable with inflammatory pseudopolyps and _________________. The tips of the pseudopolyps fuse to form _______________ - There can be extensive ________________ ulcers or flattened atrophic mucosa - Inflammation and inflammatory mediators damage the muscularis propria and disturb neuromuscular function leading to colonic dilation and toxic megacolon, which may perforate Microscopic features - Mucosal inflammation is similar to CD but is generally limited to the mucosa and ________________________ - There are crypt abscesses, ulceration, chronic mucosal damage, glandular architectural distortion and atrophy - No fissures, aphthous ulcers or granulomas are seen Clinical features - Patients present with intermittent attacks of bloody mucoid diarrhoea and abdominal pain that can persist for days to months before subsiding - Although half of patients have clinically mild disease most patients relapse between 10 years and 30% of patients require a colectomy within 3 years to control symptoms - Extra-intestinal manifestations include migratory polyarthritis, Sacroiliitis, ankylosing spondylitis, uveitis, skin lesions, pericholangitis and ________________ - There is an increased risk of colonic adenocarcinoma Indeterminate colitis  4 - There is pathological and clinical overlap between UC and CD - Definitive diagnosis is not possible in 10% of IBD patients Colitis associated neoplasia - Risk of malignancy in IBD: Increases 8 to 10 years after disease onset Is greater with ________________versus left sided only disease Increases with the severity and duration of active inflammation - Patients with long standing disease are followed by biopsy surveillance