Inflammatory Bowel Disease (IBD): Definition, Epidemiology, Pathogenesis, Clinical Presentation, and Treatment

2. Goals: learning 1. Inflammatory Bowel Disease (IBD) Definition Epidemiology Etiology and Pathogenesis Pathology Clinical Presentation Laboratory, Endoscopic, and Radiographic Features Extraintestinal Manifestations Complications Treatment 2. Irritable Bowel Syndrome (IBS) Definition Clinical Feature Pathophysiology Treatment

3. Inflammatory Bowel Disease (IBD) Definition Inflammatory bowel disease (IBD) is an immune-mediated chronic intestinal condition. Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of IBD.

4. Inflammatory bowel disease (IBD) Epidemiology The incidence of IBD varies within different geographic areas. CD and UC both occur at the highest incidence in Europe, the United Kingdom, and North America. IBD has been rare in other areas except Israel, Australia, and South Africa. The incidence of IBD, especially UC, is rising in Japan, South Korea, Singapore, northern India, and Latin America, areas previously thought to have low incidence. The highest mortality is during the first years of disease and in long-duration disease due to the risk of colon cancer. The peak age of onset of UC and CD is between 15 and 30 years. A second peak occurs between the ages of 60 and 80. The male to female ratio for UC is 1:1 and for CD is 1.1–1.8:1.

5. Inflammatory bowel disease (IBD) Etiology and Pathogenesis A consensus hypothesis is that in genetically predisposed individuals, both exogenous factors (e.g., composition of normal intestinal microbiota) and endogenous host factors (e.g., intestinal epithelial cell barrier function, innate and adaptive immune function) interact to cause a chronic state of dysregulated mucosal immune function that is further modified by specific environmental factors (e.g., smoking, enteropathogens). IBD is currently considered an inappropriate immune response to the endogenous commensalmicrobiota within the intestines, with or without some component of autoimmunity.

7. Inflammatory bowel disease (IBD) Pathology

8. Inflammatory bowel disease (IBD) Clinical Presentation Ulcerative Colitis The major symptoms of UC are diarrhea, rectal bleeding, tenesmus, passage of mucus, and crampy abdominal pain. Although UC can present acutely, symptoms usually have been present for weeks to months. Diarrhea is often nocturnal and/or postprandial. Other symptoms in moderate to severe disease include anorexia, nausea, vomiting, fever, and weight loss.

9. Inflammatory bowel disease (IBD) Clinical Presentation Crohn's Disease The site of disease influences the clinical manifestations. Ileocolitis Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. Weight loss is common—typically 10–20% of body weight—and develops as a consequence of diarrhea, anorexia, and fear of eating. Jejunoileitis Extensive inflammatory disease is associated with a loss of digestive and absorptive surface, resulting in malabsorption and steatorrhea. Nutritional deficiencies can also result from poor intake and enteric losses of protein and other nutrients. Intestinal malabsorption can cause anemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis in patients with an intact colon.

10. Inflammatory bowel disease (IBD) Clinical Presentation Crohn's Disease (continued) Colitis and Perianal Disease Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia. Gross bleeding is not as common as in UC and appears in about one-half of patients with exclusively colonic disease. Only 1–2% bleed massively. Gastroduodenal Disease Symptoms and signs of upper GI tract disease include nausea, vomiting, and epigastric pain. Patients usually have an Helicobacter pylori–negative gastritis. The second portion of the duodenum is more commonly involved than the bulb.

11. Inflammatory bowel disease (IBD) Laboratory, Endoscopic, and Radiographic Features Ulcerative Colitis Active disease can be associated with a rise in acute-phase reactants [C-reactive protein (CRP)], platelet count, erythrocyte sedimentation rate (ESR), and a decrease in hemoglobin. Fecal lactoferrin is a highly sensitive and specific marker for detecting intestinal inflammation. Diagnosis relies upon the patient's history; clinical symptoms; negative stool examination for bacteria, C. difficile toxin, and ova and parasites; sigmoidoscopic appearance; and histology of rectal or colonic biopsy specimens.

12. Inflammatory bowel disease (IBD) Laboratory, Endoscopic, & Radiographic Features Crohn's Disease Laboratory abnormalities include elevated ESR and CRP. In more severe disease, findings include hypoalbuminemia, anemia, and leukocytosis. Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Colonoscopy allows examination and biopsy of mass lesions or strictures and biopsy of the terminal ileum. Upper endoscopy is useful in diagnosing gastroduodenal involvement in patients with upper tract symptoms.

13. Inflammatory bowel disease (IBD) Extraintestinal Manifestations Up to one-third of IBD patients have at least one extraintestinal disease manifestation. Dermatologic Erythema nodosum (EN): 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. Rheumatologic Peripheral arthritis is more common in CD. It is asymmetric, polyarticular, and migratory and most often affects large joints of the upper and lower extremities. Ocular The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis.

15. Inflammatory bowel disease (IBD) Extraintestinal manifestations Hepatobiliary Hepatic steatosis: patients usually present with hepatomegaly. Fatty liver, and cholelithiasis are seen. Urologic The most frequent genitourinary complications are calculi, ureteral obstruction, and ileal bladder fistulas. Metabolic Bone Disorders Low bone mass occurs in 3–30% of IBD patients. The risk is increased by glucocorticoids, cyclosporine, methotrexate and total parenteral nutrition (TPN). Thromboembolic Disorders Patients with IBD have an increased risk of both venous and arterial thrombosis even if the disease is not active.

16. Inflammatory bowel disease (IBD) Treatment 5-ASA Agents The mainstay of therapy for mild to moderate UC is sulfasalazine and the other 5-ASA agents. These agents are effective at inducing and maintaining remission in UC. They may have a limited role in inducing remission in CD but no clear role in maintenance of CD. Sulfasalazine can impair folate absorption, and patients should be given folic acid supplements. Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. Asacol is an enteric-coated form of mesalamine with the 5-ASA being released at pH >7.

17. Inflammatory bowel disease (IBD) Treatment (continued) Glucocorticoids The majority of patients with moderate-to-severe UC and CD benefit from oral or parenteral glucocorticoids. Antibiotics Metronidazole is effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. Ciprofloxacin is also beneficial. Azathioprine and 6-Mercaptopurine They are purine analogues commonly employed in the management of glucocorticoid-dependent IBD. Cyclosporine Cyclosporine (CSA) has the inhibitory effects on both the cellular and humoral immune systems.

18. Inflammatory bowel disease (IBD) Treatment (continued) Nutritional Therapies Dietary antigens may stimulate the mucosal immune response. Patients with active CD respond to bowel rest, along with TPN. Bowel rest and TPN are as effective as glucocorticoids at inducing remission of active CD. Enteral nutrition in the form of elemental or peptide-based preparations is also as effective as glucocorticoids or TPN, but these diets are not palatable. Enteral diets may provide the small intestine with nutrients vital to cell growth and do not have the complications of TPN. In contrast to CD, dietary intervention does not reduce inflammation in UC.

21. Irritable bowel syndrome (IBS) Definition Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habits in the absence of detectable structural abnormalities. No clear diagnostic markers exist for IBS, thus the diagnosis of the disorder is based on clinical presentation. Throughout the world, about 10–20% of adults and adolescents have symptoms consistent with IBS, and most studies show a female predominance. IBS symptoms tend to come and go over time and often overlap with other functional disorders such as fibromyalgia, headache, backache, and genitourinary symptoms. Severity of symptoms varies and can significantly impair quality of life, resulting in high health care costs.

22. Irritable bowel syndrome (IBS) Clinical Features Symptoms include: 1. Pain or abdominal discomfort: is a key symptom for the diagnosis of IBS. (Pain is often exacerbated by eating or emotional stress and improved by passage of flatus or stools.) 2. Painless diarrhea or constipation : alteration in bowel habits is the most consistent clinical feature in IBS 3. Urgency or a feeling of incomplete bowel movement, 4. Bloating : Patients with IBS frequently complain of abdominal distention and increased belching or flatulence. (Although some patients with these symptoms actually may have a larger amount of gas, quantitative measurements reveal that most patients who complain of increased gas generate no more than a normal amount of intestinal gas.)

23. Irritable bowel syndrome (IBS) Clinical Features (continued) 5.Upper gastrointestinal symptoms (Between 25 and 50% of patients with IBS complain of dyspepsia, heartburn, nausea, plus vomiting.) Sleep deprivation is also unusual because abdominal pain is almost uniformly present only during waking hours. However, patients with severe IBS frequently wake repeatedly during the night; thus, nocturnal pain is a poor discriminating factor between organic and functional bowel disease. In addition, female patients with IBS commonly report worsening symptoms during the premenstrual and menstrual phases.

25. Irritable bowel syndrome (IBS) Pathophysiology 1. Gastrointestinal motor abnormalities : IBS patients may exhibit increased rectosigmoid motor activity for up to 3 h after eating. 2. Visceral hypersensitivity : IBS patients frequently exhibit exaggerated sensory responses to visceral stimulation. 3. Central neural dysregulation : The role of central nervous system (CNS) factors in the pathogenesis of IBS is strongly suggested by the clinical association of emotional disorders and stress with symptom exacerbation and the therapeutic response to therapies that act on cerebral cortical sites. 4. Abnormal psychological features : Abnormal psychiatric features are recorded in up to 80% of IBS patients; however, no single psychiatric diagnosis predominates.

26. Irritable bowel syndrome (IBS) Pathophysiology 5. Post-infectious IBS : IBS may be induced by GI infection. This group of "postinfective" IBS occurs more commonly in females and affects younger rather than older patients. The microbes involved in the initial infection are Campylobacter, Salmonella, and Shigella. 6. Mucosal inflammation : Some patients with IBS display persistent signs of low-grade mucosal inflammation with activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines. 7. Altered gut flora : A high prevalence of small intestinal bacterial overgrowth in IBS patients has been noted. 8. Abnormal Serotonin Pathways : The serotonin (5HT)-containing enterochromaffin cells in the colon are increased in a subset of IBS-D patients compared to healthy individuals or patients with ulcerative colitis.

27. Irritable bowel syndrome (IBS) Treatment Patient counseling & Dietary alterations Reassurance and careful explanation of how to avoid obvious food precipitants are important first steps in patient counseling and dietary change. Occasionally, a meticulous dietary history may reveal substances (such as coffee, disaccharides, legumes, and cabbage) that aggravate symptoms. Excessive fructose and artificial sweeteners, such as sorbitol or mannitol, may cause diarrhea, bloating, cramping or flatulence. As a therapeutic trial, patients should be encouraged to eliminate any foodstuffs that appear to produce symptoms. However patients should avoid nutritionally depleted diets.

29. Irritable bowel syndrome (IBS) Treatment(continued) Patient counseling & Dietary alterations (continued) Patients with IBS-D anecdotally report symptom improvement after initiating a low-carbohydrate diet. A prospective study has shown marked symptomatic improvement in stool frequency, consistency, pain scores, and quality of life following 4 weeks of a very-low-carbohydrate (CHO) diet (20 g CHO/day). This diet may be tried in IBS patients who report intolerance to certain carbohydrates.

30. Irritable bowel syndrome (IBS) Treatment (continued) Stool-bulking agents High-fiber diets and bulking agents, such as bran, are frequently used in treating IBS. The water-holding action of fibers may contribute to increased stool bulk because of the ability of fiber to increase fecal output of bacteria. Fiber also speeds up colonic transit in most persons. In diarrhea-prone patients, whole-colonic transit is faster than average; however, dietary fiber can delay transit. Furthermore, because of their hydrophilic properties, stool-bulking agents bind water and thus prevent both excessive hydration and dehydration of stool. The latter observation may explain the clinical experience that a high-fiber diet relieves diarrhea in some IBS patients.

31. Irritable bowel syndrome (IBS) Treatment (continued) Stool-bulking agents (continued) Fiber supplementation with psyllium has been shown to reduce perception of rectal distention, indicating that fiber may have a positive effect on visceral afferent function. psyllium produced greater improvements in stool pattern and abdominal pain than bran. Furthermore, psyllium preparations tend to produce less bloating and distention. Despite the equivocal data regarding efficacy, most gastroenterologists consider stool-bulking agents worth trying in patients with IBS-C.

32. Irritable bowel syndrome (IBS) Treatment (continued) Antispasmodics Clinicians have observed that anticholinergic drugs may provide temporary relief for symptoms such as painful cramps related to intestinal spasm. Some physicians prefer to use synthetic anticholinergics such as dicyclomine that have less effect on mucous membrane secretions and produce fewer undesirable side effects. Antidiarrheal agents Peripherally acting opiate-based agents are the initial therapy of choice for IBS-D. When diarrhea is severe, especially in the painless diarrhea variant of IBS, small doses of loperamide, 2–4 mg every 4–6 h up to a maximum of 12 g/d, can be prescribed. These agents are less addictive than paregoric, codeine, or tincture of opium.

33. Irritable bowel syndrome (IBS) Treatment (continued) Antidepressant drugs In addition to their mood-elevating effects, antidepressant medications have several physiologic effects that suggest they may be beneficial in IBS. In IBS-D patients, the tricyclic antidepressant imipramine slows jejunal migrating motor complex transit propagation and delays orocecal and whole-gut transit, indicative of a motor inhibitory effect.

34. Irritable bowel syndrome (IBS) Treatment (continued) Antiflatulence therapy Patients should be advised to eat slowly and not chew gum or drink carbonated beverages. If bloating is accompanied by diarrhea and worsens after ingesting dairy products, fresh fruits, vegetables, or juices, further investigation or a dietary exclusion trial may be worthwhile. Antibiotics may help in a subgroup of IBS patients with predominant symptoms of bloating. Pancreatic enzymes reduce bloating, gas, and fullness during and after high-calorie, high-fat meal ingestion.

35. Irritable bowel syndrome (IBS) Treatment (continued) Modulation of Gut Flora Antibiotic treatment benefits a subset of IBS patients. Neomycin dosed at 500 mg twice daily for 10 days was more effective. The non-absorbed oral antibiotic rifaximin is the most thoroughly studied antibiotic for the treatment of IBS. Rifaximin is the only antibiotic with demonstrated sustained benefit beyond therapy cessation in IBS patients. Since altered colonic flora may contribute to the pathogenesis of IBS, this has led to great interest in using probiotics to naturally alter the flora. Bifidobacterium infantis 35624 showed significant improvement in the composite score for abdominal pain, bloating/distention, and/or bowel movement compared with placebo in two placebo-controlled trials.

36. Inflammatory bowel disease (IBD) Some mechanisms for further information The highest frequency of nephrolithiasis (10–20%) occurs in patients with CD following small bowel resection. Calcium oxalate stones develop secondary to hyperoxaluria, which results from increased absorption of dietary oxalate. 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 leave oxalate unbound. The unbound oxalate is then delivered to the colon, where it is readily absorbed, especially in the presence of inflammation.