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Inflammatory Bowel Disease E Rahimi, MD Assiatant Professor Department Of Internal Medicine MUK Inflammatory Bowel Disease (IBD) Ulcerative colitis and Crohn's disease Chronic inflammatory diseases of the gastrointestinal tract No single finding is diagnostic for these diseases Epidemiological, clinical, laboratory, imaging and pathological characteristics Some patients have a clinical picture that falls between the two diseases Introduction IBD characterized by a tendency for chronic or relapsing immune activation and inflammation within the GIT. Crohn’s disease (CD) and ulcerative colitis (UC) are the 2 major forms of idiopathic IBD. Less common entities are: Others Microscopic colitis (collagenous and lynphocytic) Diversion colitis Radiation colitis Drug induced colitis Infectious colitis Ischemic colitis Introduction CD UC • is a condition of chronic inflammation potentially involving any location of the GIT from mouth to anus. • UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon. IBD: Systemic Complications Eye inflammation* Lower bone density* Liver and bile duct inflammation Gallstones Skin lesions *Higher incidence in women. Growth failure in children Kidney stones Subfertility* Ovaries Uterus Arthritis and joint pains Epidemiology CD: • 1st peak 15-30 years of age, 2nd peak around 60 y UC: • High incidence areas: US, UK, northern Europe • Young adults, commoner in females Epidemiology Genetics Studies suggested that 1st degree relatives of an affected patient have a risk of IBD that is 4-20 times higher than that of general population. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. Having one copy of the risk alleles confers a 2–4-fold risk for developing CD, whereas double-dose carriage increases the risk 20–40-fold. Etiology Mutations within the NOD2/ CARD15 gene contribute to CD susceptibility. inappropriate responses to bacterial Initiating pathogen? Infectious? the development and persistence of intestinal inflammation. ? Possibly nonpathogenic commensal enteric flora Pathogenesis The mucosa of CD patients is dominated by Th1 (T helper), which produce interferon-γ and IL-2. In contrast, UC dominated by Th2 phenotype, which produce transforming growth factor (TGF-) and IL-5. Activation of Th1 cells produce the down-regulatory cytokines IL-10 and TGF-. Pathogenesis A sequential casιade of inflammatory mediators extends the response; each step is a potential target for therapy. Inflammatory cytokines such as IL- l , IL-6, and TNF have divers, effects on tissues. They promote fibrogenesis, collagen production activation of tissue metalloproteinases, and the production of other inflammatory mediators; they also activate the coagulation cascade. Pathogenesis These cytokines are normally produced in response to infection but are usually turned off or inhibited at the appropriate time to limit tissue damage. In IBD their activity is not regulated, resulting in an imbalance between the proinflammatory and antiinflammatory medíators. Therapíes such as the 5 – aminosalicylic acid (5 ASA) compounds and glucocorticoids are potent inhibitors Environmental Precipitants Factors: NSAIDs use (?altered intestinal barrier), and Early appendectomy (increase UC incidence) Smoking (protects against UC but increases the risk of CD). CD: PATHOLOGY Early Findings: Aphthous ulcer. The presence of granulomas Late findings: Linear ulcers. The classic cobble stoned appearance may arise. Transmural inflammation Sinus tracts, and strictures. Fibrosis. UC: PATHOLOGY The inflammation is predominantly confined to the mucosa. Non-specific (can be seen with any acute inflammation) The lamina propria becomes edematous. Inflammatory infiltrate of neutrophils Neutrophils invade crypts, causing cryptitis & ultimately crypt abscesses. Specific (suggest chronicity): Distorted crypt architecture, crypt atrophy and a chronic inflammatory infiltrate. UC Diagnosis Exclude other possibilities (need good history, physical exam, labs, imaging and endoscopy with biopsy) There are many distinguishing features of CD and UC. In about 5% it is classified as indeterminate because of overlapping features. Distinguishing characteristics of CD and UC Feature Location CD SB or colon Rectal spare UC Only colon (rarely “backwash ileitis” Continuous, begins distally Involved in >90% Anatomic distribution Rectal involvement Gross bleeding Peri-anal disease Fistulization Granulomas Skip lesions Only 25% 75% Yes 50-75% Universal Rare No No Endoscopic features of CD and UC Feature Mucosal involvement Aphthous ulcers CD Discontinuous UC Continuous Common Rare Surrounding mucosa Longitudinal ulcer Cobble stoning Mucosal friability Vascular pattern Relatively normal Common In severe cases Uncommon Normal Abnormal Rare No Common distorted Pathologic features of CD and UC Feature Transmural inflammation CD Yes UC Uncommon Granulomas 50-75% No Fissures Fibrosis Submucosal inflammation Common Common Common Rare No Uncommon Radiologic features of CD and UC Feature CD UC Nodularity granularity cobble stoning string sign of SB Collar button ulcers UC CD UC: Presentation Must exclude infectious cause before making Dx. Rectal Bleeding Diarrhea: Abdominal Pain: frequent passage of loose or liquid stool, often associated with passing large quantities of mucus. it is not a prominent symptom. Anorexia, nausea, fever… DDX of UC Infectious Drug induced Microscopic colitis UC: Presentation UC: Presentation About 40-50% of patients have disease limited to the rectum and rectosigmoid 30-40% have disease extending beyond the sigmoid but not involving the whole colon 20% have a total colitis. CD Anatomic distribution CD activity index DDx (lymphoma, Yersinea Enterocolitis, TB) CD: clinical presentations Disease of the ileum: May present initially with a small bowel obstruction. Patients with an active disease often present with anorexia, loose stools, and weight loss. Perianal disease In 24% of patients with CD. Skin lesions include superficial ulcers, and abscesses. Anal canal lesions include fissures, ulcers, and stenosis. CD ilitis: DDx Lymphoma Yersinea TB Enterocolitis and CD: clinical presentations colonic disease The typical presenting symptom is diarrhea, occasionally with passage of obvious blood. proctitis May be the initial presentation in some cases of CD Extra-intestinal manifestations of IBD Arthritis: Peripheral arthritis, usu paralels the disease activity Ankylosing Spondylitis, 1-6%, sacroiliitis Ocular lesions: Iritis (uvietis) (0.5-3%), episcleritis, keratitis, Skin and oral cavity: Erythema nodosum 1-3% Pyoderma Gangrenosum 0.6% Aphthus stomatitis, metastatic CD. Dermatologic Erythema nodosum (EN) occurs in up to 15% of CD patients and 10% of UC patients. Attacks usually correlate with bowel activity; skin lesions develop after the onset of bowel symptoms, and patients frequently have concomitant active peripheral arthritis. The lesions of EN are hot, red, tender nodules measuring 1-5 cm in diameter and are found on the anterior surface of the lower legs , ankles, calves, thighs,and arms. Therapy is directed toward theunderlying bowel disease. Dermatologic Pyoderma gangrenosum (PG) is seen in 1 12% of UC patients and less ιommonly in Crohn's ιolitis. Although it usually presents after the diagnosis of IBD. PG may occur years before the onset of bowel symptoms A course independent of the bowel disease, respond poorly to colectomy, and even develop years after proctocolectomy. Dermatologic It is usually associated with severe disease. Lesions are commonly found on the dorsal surface of the feet and legs but may occur on the arms,chest, stoma, and even the face. PG usually begins as a pustule andthen spreads concentrically to rapidly undermine healthy skin. Lesions then ulcerate, with violaceous edges surrounded by a margin of erythema. Centrally, they contain necrotic tissue with blood and exudates. Dermatologic Lesions may be single or multiple and grow as large as 30 cm. They are sometimes very difficult to treat and often require IV antibiotics, IV glucocorticoid, dapsone, azathioprine, thalidomide, IV cyclosporine,or infliximab Dermatologic Other dermatologic manifestations include pyoderma vegetans,which occurs in intertriginous areas. Pyostomatitis vegetans, which involves the mucous membranes. Sweet syndrome, a neutrophilic dermatosis. metastatic CD, a rare disorder defined by cutaneous granuloma formation. Dermatologic Psoriasis affects 5 - 1 0% of patients with IBD and is unrelated to bowel activity consistent with the potential shared immunogenetic basis of these diseases. Perianal skin tags are found in 75-80% of patients with CD, especially those with colon involvement. Oral mucosal lesions, seen often in CD and rarely in UC, include aphthous stomatitis and cobblestone" lesions of the buccal mucosa. Rheumatologic Peripheral arthritis develops in 1 5-20% of IBD patients, is more common in CD, and worsens with exacerbations of bowel activity. It is asymmetric, polyarticular, and migratory and most often affects large joints of the upper and lower extremities. Treatment is directed at reducing bowel inflammation. In severe UC, colectomy frequently cures the arthritis. Rheumatologic Ankylosing spondylitis (AS) occurs in about 10% of IBD patients and is more common in CD than Uc. About two-thirds of IBD patients with AS express the HLA-B27 antigen. The AS activity is not related to bowel activity and does not remit with glucocorticoids or colectomy. It most often affects the spine and pelvis, producing symptoms of diffuse low-back pain, buttock pain, and morning stiffness. Rheumatologic The course is continuous and progressive, leading to permanent skeletal damage and deformity. Anti-TNF therapy reduces spinal inflammation and improves functional status and quality of life. Sacroiliitis is symmetric, occurs equally in UC and CD, is often asymptomatic, does not correlate with bowel activity, and does not always progress to AS. Rheumatologic Other rheumatic manifestations include hyper trophic osteoarthropathy, pelvic!femoral osteomyelitis, and relapsing polychondritis. Ocular The incidence of ocular complications in IBD patients is 1 - 1 0%. The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis. Uveitis is associated with both UC and Crohn's colitis may be found during periods of remission may develop in patients following bowel resection. Symptoms include ocular pain, photophobia, blurred vision, and headache. Ocular Prompt intervention, sometimes with systemic glucocorticoids, is required to prevent scarring and visual impairment. Ocular Episderitis is a benign disorder that presents with synptoms of mild ocular burning. It occurs in 3-4% of IBD patients more commonly in Crohn's colitis is treated with topical glucocorticoids Hepatobiliary Hepatic steatosis is detectable in about onehalf of the abnormal liver biopsies from patients with CD and UC; patients usually present with hepatomegaly. Fatty liver usually results from a combination of chronic debilitating illness, malnutrition, and glucocorticoid therapy. Cholelithiasis occurs in 10-35% of CD patients with ileitis or ileal resection. Hepatobiliary Gallstone formation is caused by malabsorption of bile acids, resulting in depletion of the bile salt pool and the secretion of lithogenic bile. Primary sclerosing cholangitis (PSC) is a disorder characterized by both intrahepatic and extrahepatic bile duct inflammation and fibrosis. Frequently leading to biliary cirrhosis and hepatic failure. 5% of patients with UC have PSC, but 50-75% of patients with PSC have IBD. Hepatobiliary PSC occurs less often in patients with CD. Although it can be recognized after the diagnosis of IBD PSC can be detected earlier or even years after proctocolectomy. Consistent with this, the immunogenetic basis for PSC appears to be overlapping IBD and PSC are commonly pANCA positive. Hepatobiliary Most patients have no symptoms at the time of diagnosis; when symptoms are present, they consist of fatigue, jaundice, abdominal pain, fever, anorexia, and malaise. The traditional gold standard diagnostic test is endoscopic retrograde cholangiopancrea tography (ERCP) magnetic resonance cholangiopancreatography (MRCP) is also sensitive and specific. MRCP is reasonable as an initial diagnostic test in children and. Hepatobiliary In patients with PSC. both ERCP and MRCP demonstrate multiple bile duct strictures alternating with relatively normal segments. The bile acid ursodeoxycholic acid (ursodiol) may reduce alkaline phosphatase and serum aminotransferase levels, but histologic improvement has been marginal. High doses (25-30 mg/kg per day) may decrease the risk of colorectal dysplasia and cancer in patientswith UC and PSc. Hepatobiliary Endoscopic stenting may be palliative for cholestasis secondary to bile duct obstruction. Patients with symptomatic disease develop cirrhosis and liver failure over 5 - 1 0 years and eventually require liver transplantation. PSC patients have a 10- 1 5% lifetime risk of developing cholangiocarcinoma and then cannot be transplanted Patients with IBD and PSC are at increased risk of colon cancer and should be surveyed yearly by colonoscopy and biopsy. Hepatobiliary Cholangiography is normal in a small percentage of patients who have a variant of PSC known as small duct primary sclerosing cholangitis. This variant (sometimes referred to as "pericholangitis") is probably a form of PSC involving small-caliber bile ducts. It has similar biochemical and histologic features to classic PSc. It appears to have a significantly better prognosis than classic PSC, although it may evolve into classic PSc. Hepatobiliary Granulomatous hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD. Urologic The most frequent genitourinary complications are calculi, ureteral obstruction, and ileal bladder fistulas. The highest frequency of nephrolithiasis ( 1 020%) occurs in patients with CD following small bowelresection. Calcium oxalate stones develop secondary to hyperoxaluria,which results from increased absorption of dietary oxalate. Urologic Normally,dietary calcium combines with luminal oxalate to form insoluble calcium oxalate, which is eliminated in the stool. In patients with ileal dysfunction, however, nonabsorbed fatty acids bind calcium and leaveoxalate unbound. The unbound oxalate is then delivered to the colon, where it is readily absorbed, especially in the presence of inflammation hepatitis and hepatic amyloidosis are much rarer extraintestinal manifestations of IBD. Metabolic Bone Disease Low bone mass occurs in 3-30% of IBD patients. The risk is increased by glucocorticoids, cyclosporine, methotrexate, and total parenteral nutrition (TPN) . Malabsorption and inflammation mediated by IL- 1 ,IL 6, TNF, and other inflammatory mediators also contribute t o low bone density. An increased incidence of hip, spine, wrist, and rib fractures has been noted: 36% in CD and 45% in Uc. Metabolic Bone Disease The absolute risk of an osteoporotic fracture is about 1 % per person per year. Fracture rates, particularly in the spine and hip , are highest among the elderly (age >60). One study noted an OR of 1 .72 for vertebral fracture and an OR of 1 .59 for hip fracture. The disease severity predicted the risk of a fracture. Only 1 3 % of IBD patients who had a fracture were on any kind of antifracture treatment. Metabolic Bone Disease Up to 20% of bone mass can be lost per year with chronic glucocorticoid use. The effect is dosage-dependent. Budesonide may also suppress the pituitaryadrenal axis and thus carries a risk of causing osteoporosis. Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse. Metabolic Bone Disease The pain is aggravated by motion and swelling of the joints. It affects the hips more often than knees and shoulders, and in one series, 4.3% of patients developed osteonecrosis within 6 months of starting glucocorticoids. Diagnosis is made by bone scan or MRI, and treatment consists of pain control, cord decompression,osteotomy, and joint replacement. Thromboembolic Disorder Patients with IBD risk of both venous and arterial thrombosis even if the disease is not active. Factors responsible for the hypercoagulable state: d: abnormalities of the plateletendothelial interaction Hyperhomocysteinemia alterations in the coagulation cascade impaired fibrinolysis involvement of tissue factor-bearing microvesicles disruption of coagulation system by autoantibodies genetic predisposition. A spectrum of vasculitides involving small, medium, and large vessels has also been observed. Extra-intestinal manifestations of IBD Liver and Biliary tract disease: Pericholangitis, fatty infiltration, PSC (1-4%, more with UC), cholangiocarcinoma, gallstones Thromboembolic disease, vasculitis, Renal disease (urolithiasis, GN), clubbing, amyloidosis. IBD: Systemic Complications Eye inflammation* Lower bone density* Liver and bile duct inflammation Gallstones Skin lesions *Higher incidence in women. Growth failure in children Kidney stones Subfertility* Ovaries Uterus Arthritis and joint pains Complications of IBD Bleeding Stricture Fistula Toxic megacolon Cancer Complications of IBD Treatment Goals of therapy Induce and maintain remission. Ameliorate symptoms Improve pts quality of life Adequate nutrition Prevent complication of both the disease and medications 5-Aminosalicylic Acids The mainstay treatment of mild to moderately active UC and CD (induction). 5-ASA may act by blocking the production of prostaglandins and leukotrienes, inhibiting bacterial peptide–induced neutrophil chemotaxis and adenosine-induced secretion, scavenging reactive oxygen metabolites 5-Aminosalicylic Acids For patients with distal colonic disease, a suppository or enema form will be most appropriate. Maintenance treatment with a 5-aminosalicylic acid can be effective for sustaining remission in ulcerative colitis but is of questionable value in Crohn's disease. Corticosteroids Topical corticosteroids can be used as an alternative to 5-ASA in ulcerative proctitis or distal UC. Oral prednisone or prednisolone is used for moderately severe UC or CD, in doses ranging up to 60 mg per day. IV is warranted for patients who are sufficiently ill to require hospitalization; the majority will have a response within 7 to 10 days. Corticosteroids No proven maintenance benefit in the treatment of either UC or CD. Many and serious side effects. Budesonide: less side effects, its use is limited to patients with distal ileal and rightsided colonic disease Immunosuppressive Agents These agents are generally appropriate for patients in whom the dose of corticosteroids cannot be tapered or discontinued. Azathioprine & 6-MP The most extensively used immunosuppressive agents. The mechanisms of action unknown but may include suppressing the generation of a specific subgroup of T cells. The onset of benefit takes several weeks up to six months. Dose-related BM suppression is uniformly observed Immunosuppressive Agents Methotrexate Effective in steroid-dependent active CD and in maintaining remission. Cyclosporine Severe UC not responding to IV steroid &need urgent proctocolectomy. 50% of the responders will need surgery within a year. Anti-TNF Therapy: Infliximab It is a chimeric monoclonal antibody, binds soluble TNF. Prompt onset, effects takes 6weeks to max of 6m. Indicated in fisulizing crohns, refractory CD and refractory UC Complications (it is safe and usu tolerable) Acute infusion reactions, which may include chest tightness, dyspnea, rash, and hypotension. Delayed hypersensitivity reactions, consisting of severe polyarthralgia, myalgia, facial edema, urticaria, or rash, are an unusual complication occurring from 3 to 12 days after an infusion. Infliximab: side effects Increase risk of upper respiratory infections. Any patient suspected of having a pyogenic complication of CD or any serious infection should undergo adequate drainage and treatment with antibiotics before starting infliximab. Reactivation of tuberculosis has been observed and has resulted in disseminated disease and death. INDICATIONS FOR SURGERY In patients with UC: Severe attacks that fail to respond to medical therapy. Complications of a severe attack (e.g., perforation, acute dilatation). Chronic continuous disease with an impaired quality of life. Dysplasia or carcinoma. In patients with CD Obstruction, severe perianal disease unresponsive to medical therapy, difficult fistulas, major bleeding, severe disability 30 % relapse rate IBD Sequelae UC: Risk of cancer begins after 8 years, risk of pancolitis 7% at 20 years and 17% at 30 years. Increased risk: early age of onset, pancolitis. Need for colonoscopic screening after 8 years CD: True incidence of cancer is uncertain, but could be as high as UC Need the same screening policy. IBD conclusion It is a chronic disorders Need to exclude other possibilities Need to differentiate between the two Need long term management with primary goal to induce then maintain remission and prevent complications of both the disease and drugs.