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Inflammatory Bowel Disease, Irritable Bowel Syndrome

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  • Oral contraceptives are also linked to CD; the odds ratio of CD for oral contraceptive users is about 1.4.
  • Additional evidence for genetic predisposition to IBD comes from its association with certain genetic syndromes.
  • IBD is currently considered an inappropriate immune response to the endogenous commensal microbiota within the intestines, with or without some component of autoimmunity.During the course of infections in the normal host, full activation of the gut-associated lymphoid tissues occurs but is rapidly superseded by dampening of the immune response and tissue repair. In IBD this process may not be regulated normally.
  • IBD is a polygenic disorder that gives rise to multiple clinical subgroups within UC and CD. A variety of genetic approaches including candidate gene studies, linkage analysis and genome-wide association studies that focus on the identification of disease-associated, single-nucleotide polymorphisms (SNP) within the human genome have identified approximately 100 disease-associated loci on many different chromosomes.
  • The mucosal immune system is normally unreactive to luminal contents due to oral (mucosal) tolerance. Oral tolerance may be responsible for the lack of immune responsiveness to dietary antigens and the commensal microbiota in the intestinal lumen. In IBD this suppression of inflammation is altered, leading to uncontrolled inflammation.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 anti-inflammatory mediators. Observational studies suggest that multiple pathogens (e.g., Salmonella, Shigella, Campylobacter, Clostridium difficile spp.) may initiate IBD by triggering an inflammatory response that the mucosal immune system may fail to control. However, in an IBD patient, the normal microbiota is likely perceived inappropriately as if it were a pathogen.
  • UC is a mucosal disease that usually involves the rectUmand extends proximally to involve all or part of the colon. 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, and 20% have a total colitis.With mild inflammation, the mucosa is erythematous and has a fine granular surface that resembles sandpaper. In more severe disease, the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 295-1) In long-standing disease, inflammatory polyps (pseudopolyps) may be present as a result of epithelial regeneration. The mucosa may appear normal in remission, but in patients with many years of disease it appears atrophic and featureless, and the entire colon becomes narrowed and shortened. Patients with fulminant disease can develop a toxic colitis or megacolon where the bowel wall thins and the mucosa is severely ulcerated; this may lead to perforation.
  • CD can affect any part of the GI tract from the mouth to the anus. Some 30–40% of patients have small bowel disease alone, 40–55% have disease involving both the small and large intestines, and 15–25% have colitis alone. In the 75% of patients with small intestinal disease, the terminal ileum is involved in 90%. Unlike UC, which almost always involves the rectum, the rectum is often spared in CD. CD is segmental with skip areas in the midst of diseased intestine.Perirectal fistulas, fissures, abscesses, and anal stenosis are present in one-third of patients with CD, particularly those with colonic involvement. Rarely, CD may also involve the liver and the pancreas.Unlike UC, CD is a transmural process. Endoscopically, aphthous or small superficial ulcerations characterize mild disease; in more active disease, stellate ulcerations fuse longitudinally and transversely to demarcate islands of mucosa that frequently are histologically normal. This "cobblestone" appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form in CD.Active CD is characterized by focal inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel. The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel ("creeping fat"), and serosal and mesenteric inflammation promotes adhesions and fistula formation.
  • The process is limited to the mucosa and superficial submucosaTwo major histologic features suggest chronicity and help distinguish it from infectious or acute self-limited colitis. First, the crypt architecture of the colon is distorted; crypts may be bifid and reduced in number, often with a gap between the crypt bases and the muscularis mucosae. Second, some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion, with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present. The neutrophils invade the epithelium, usually in the crypts, giving rise to cryptitis and, ultimately, to crypt abscesses
  • The earliest lesions are aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages, which form noncaseating granulomas in all layers of the bowel wall. Granulomas can be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. Although granulomas are a pathognomonic feature of CD, they are rarely found on mucosal biopsies. Surgical resection reveals granulomas in about one-half of cases. Other histologic features of CD include submucosal or subserosal lymphoid aggregates, particularly away from areas of ulceration, gross and microscopic skip areas, and transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall and sometimes form fistulous tracts or local abscesses.
  • Sigmoidoscopy is used to assess disease activity and is usually performed before treatment. If the patient is not having an acute flare, colonoscopy is used to assess disease extent and activity.Endoscopically mild disease is characterized by erythema, decreased vascular pattern, and mild friability. Moderate disease is characterized by marked erythema, absent vascular pattern, friability and erosions, and severe disease by spontaneous bleeding and ulcerations.
  • The earliest radiologic change of UC seen on single-contrast barium enema is a fine mucosal granularity. With increasing severity, the mucosa becomes thickened, and superficial ulcers are seen. Deep ulcerations can appear as "collar-button" ulcers, which indicate that the ulceration has penetrated the mucosa. Haustral folds may be normal in mild disease, but as activity progresses they become edematous and thickened. Loss of haustration can occur, especially in patients with long-standing disease. In addition, the colon becomes shortened and narrowed. Polyps in the colon may be postinflammatory polyps or pseudopolyps, adenomatous polyps, or carcinoma.
  • Once a diagnosis of IBD is made, distinguishing between UC and CD is impossible initially in up to 15% of cases. These are termed indeterminate colitis. Fortunately, in most cases, the true nature of the underlying colitis becomes evident later in the course of the patient's disease. Approximately 5% (range 1–20%) of colon resection specimens are difficult to classify as either UC or CD because they exhibit overlapping histologic features.The other differentials would include the ff:
  • Up to one-third of IBD patients have at least one extraintestinal disease manifestation.
  • Once a diagnosis of IBD is made, distinguishing between UC and CD is impossible initially in up to 15% of cases. These are termed indeterminate colitis. Fortunately, in most cases, the true nature of the underlying colitis becomes evident later in the course of the patient's disease. Approximately 5% (range 1–20%) of colon resection specimens are difficult to classify as either UC or CD because they exhibit overlapping histologic features.The other differentials would include the ff:
  • The majority of patients with moderate-to-severe UC benefit from oral or parenteral glucocorticoids.Prednisone is usually started at doses of 40–60 mg/d for active UC that is unresponsive to 5-ASA therapy. Parenteral glucocorticoids may be administered as hydrocortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d.
  • Antibiotics have no role in the treatment of active or quiescent UC however.Metronidazole is effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. The most effective dose is 15–20 mg/kg per day in three divided doses; it is usually continued for several months.
  • Nearly one-half of patients with extensive chronic UC undergo surgery within the first 10 years of their illness. The indications for surgery are listed in Table 295-8.Morbidity is about 20% in elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and sepsis, and neural injury. The operation of choice is an IPAA.
  • No clear diagnostic markers exist for IBS, thus the diagnosis of the disorder is based on clinical presentation.
  • Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis
  • IBS-C (constipation), IBS-D, IBS-M
  • Prevalence of IBS is 31.7% higher among patients with dyspepsia. Conversely among patients with IBS, 55.6% of patients report symptoms of dyspepsia.
  • It has been proposed that these exaggerated responses may be due to (1) increased end-organ sensitivity with recruitment of "silent" nociceptors; (2) spinal hyperexcitability with activation of nitric oxide and possibly other neurotransmitters; (3) endogenous (cortical and brainstem) modulation of caudad nociceptive transmission; and (4) over time, the possible development of long-term hyperalgesia due to development of neuroplasticity, resulting in permanent or semipermanent changes in neural responses to chronic or recurrent visceral stimulation.
  • In addition, IBS patients also show preferential activation of the prefrontal lobe, which contains a vigilance network within the brain that increases alertness. These may represent a form of cerebral dysfunction leading to the increased perception of visceral pain.
  • Brain functional MRI studies show greater activation of the posterior and middle dorsal cingulate cortex, which is implicated in affect processing in IBS patients with a past history of sexual abuse.Patients with IBS frequently demonstrate increased motor reactivity of the colon and small bowel to a variety of stimuli and altered visceral sensation associated with lowered sensation thresholds. These may result from CNS—enteric nervous system dysregulation.
  • These may result from CNS—enteric nervous system dysregulation.Patients with mild to moderate symptoms usually have intermittent symptoms that correlate with altered gut physiology. Treatments include gut-acting pharmacologic agents such as antispasmodics, antidiarrheals, fiber supplements, and gut serotonin modulators. Patients who have severe symptoms usually have constant pain and psychosocial difficulties. This group of patients is best managed with antidepressants and other psychosocial treatments. CNS, central nervous system; ENS, enteric nervous system.
  • IBS may be induced by GI infection. This group of "postinfective" IBS occurs more commonly in females and affects younger rather than older patients. Risk factors for developing post-infectious IBS include, in order of importance, prolonged duration of initial illness, toxicity of infecting bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse-life events in the preceding 3 months. Age older than 60 years might protect against post-infectious IBS, whereas treatment with antibiotics has been associated with increased risk. The microbes involved in the initial infection are Campylobacter, Salmonella, and Shigella. Those patients with Campylobacter infection who are toxin-positive are more likely to develop postinfective IBS. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability are acute changes following Campylobacter enteritis that could persist for more than a year and may contribute to postinfective IBS.
  • Some patients with IBS display persistent signs of low-grade mucosal inflammation with activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines. These abnormalities may contribute to abnormal epithelial secretion and visceral hypersensitivity. Interestingly, clinical studies have shown increased intestinal permeability in patients with IBS-D. Psychological stress and anxiety can increase the release of proinflammatory cytokine and this in turn may alter intestinal permeability. This provides a functional link between psychological stress, immune activation, and symptom generation in patients with IBS.
  • A high prevalence of small intestinal bacterial overgrowth in IBS patients has been noted based on positive lactulose hydrogen breath test. A number of studies found significant differences between the molecular profile of the fecal microbiota of IBS patients compared with that of healthy subjects. Several bacterial genera with Lactobacillus sequence appear to be absent from IBS, and Collinsella sequences were greatly reduced in this group of patients. It is unclear whether such changes are causal, consequential, or merely the result of constipation and diarrhea.
  • 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. Furthermore, postprandial plasma 5HT levels were significantly higher in this group of patients compared to healthy controls. Since serotonin plays an important role in the regulation of GI motility and visceral perception, the increased release of serotonin may contribute to the postprandial symptoms of these patients and provides a rationale for the use of serotonin antagonists in the treatment of this disorder.
  • Clinical features suggestive of IBS include the following: recurrence of lower abdominal pain with altered bowel habits over a period of time without progressive deterioration, onset of symptoms during periods of stress or emotional upset, absence of other systemic symptoms such as fever and weight loss, and small-volume stool without any evidence of blood.On the other hand, the appearance of the disorder for the first time in old age, progressive course from time of onset, persistent diarrhea after a 48-h fast, and presence of nocturnal diarrhea or steatorrheal stools argue against the diagnosis of IBS.
  • a younger individual with mild symptoms requires a minimal diagnostic evaluation, while an older person or an individual with rapidly progressive symptoms should undergo a more thorough exclusion of organic disease. Most patients should have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not responding to simple anti-diarrhea agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis.
  • a younger individual with mild symptoms requires a minimal diagnostic evaluation, while an older person or an individual with rapidly progressive symptoms should undergo a more thorough exclusion of organic disease. Most patients should have a complete blood count and sigmoidoscopic examination; in addition, stool specimens should be examined for ova and parasites in those who have diarrhea. In patients with persistent diarrhea not responding to simple anti-diarrhea agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis. In those aged >40 years, an air-contrast barium enema or colonoscopy should also be performed. If the main symptoms are diarrhea and increased gas, the possibility of lactase deficiency should be ruled out with a hydrogen breath test or with evaluation after a 3-week lactose-free 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).
  • Transcript

    • 1. Harrison’s Club:InflammatoryBowel DiseaseMarica A. Lazo
    • 2. Inflammatory Bowel Disease• Immune-mediated chronic intestinal condition• 2 major types: Ulcerative colitis (UC) and Crohn’s disease (CD)• Highest incidence in Europe, the United Kingdom, and North America• Urban areas have a higher prevalence of IBD than rural areas, and high socioeconomic classes have a higher prevalence than lower socioeconomic classes
    • 3. Epidemiology
    • 4. Genetic Disorders Associated with IBD
    • 5. Etiology and Pathogenesis In genetically predisposed individuals, exogenous factors (e.g., composition of normal intestinal microbiota) + endogenous host factors (e.g., intestinal epithelial cell barrier function, innate and adaptive immune function)chronic state of dysregulated mucosal immune function that is further modified by specific environmental factors (e.g., smoking, enteropathogens)
    • 6. Genetic Considerations• The diseases and the genetic risk factors that are shared with IBD include rheumatoid arthritis (TNFAIP3), psoriasis (IL23R,IL12B), ankylosing spondylitis (IL23R), type 1 diabetes mellitus (IL10,PTPN2), asthma (ORMDL3), and systemic lupus erythematosus (TNFAIP3,IL10)
    • 7. Genetic Considerations• Defective Immune regulation • Suppression of inflammation is altered  uncontrolled inflammation• Inflammatory cascade • Cytokine activity not regulated  imbalance between proinflammatory and anti- inflammatory mediators• Exogenous factors • Normal microbiota is perceived inappropriately as if it were a pathogen
    • 8. Pathology
    • 9. Ulcerative Colitis – Macroscopic Features
    • 10. Crohn’s Disease – Macroscopic Features
    • 11. Macroscopic Features UC CD Rectal involvement   Pseudopolyps   Toxic megacolon   Skip lesions   Perirectal fistulas, fissures,  abscesses, and anal stenosis Transmural involvement   Cobblestone appearance  
    • 12. Ulcerative Colitis – Microscopic Features
    • 13. Crohn’s Disease – Microscopic Features
    • 14. Only GALS can be Crohn’s!G – GranulomasAL – All Layers and All LevelsS – Skip lesions
    • 15. Clinical Presentation
    • 16. Clinical Features of UC vs CD
    • 17. Endoscopic and Radiographic Features ofUC vs CD
    • 18. Differential Diagnosis of UCand CD
    • 19. Diseases that Mimic IBD
    • 20. Diseases that Mimic IBD
    • 21. Extraintestinal Manifestations• Dermatologic• Rheumatologic• Ocular• Hepatobiliary• Urologic• Metabolic bone disorders• Thromboembolic disorders• Others
    • 22. Extraintestinal Manifestations:A PIE SAC• Aphthous ulcers• Pyoderma gangrenosum• Iritis• Erythema nodosum• Sclerosing cholangitis• Arthritis• Clubbing of fingertips
    • 23. Treatment of IBD
    • 24. Treatment• 5-ASA Agents • Mainstay of therapy for mild to moderate UC is Sulfasalazine and other 5-ASA agents. Limited role in inducing remission in CD.
    • 25. Treatment• Glucocorticoids • For moderate to severe UC and CD • Prednisone 40–60 mg/d for active UC that is unresponsive to 5-ASA therapy. • Parenteral: hydrocortisone, 300 mg/d, or methylprednisolone, 40–60 mg/d. • No role in maintenance therapy for both UC and CD
    • 26. Treatment• Antibiotics • Pouchitis in 1/3 of UC patients post colectomy = responsive to metronidazole and/or ciprofloxacin • Metronidazole • Effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. • The most effective dose is 15–20 mg/kg per day in three divided doses; it is usually continued for several months.
    • 27. Treatment• Azathioprine• 6-Mercaptopurine• Methotrexate• Cyclosporine• Tacrolimus• Biologic therapies • Anti-TNF therapies • Natalizumab
    • 28. Standard Medical Management of UC
    • 29. Standard Medical Management of CD
    • 30. Indications for Surgery
    • 31. Harrison’s Club:Irritable BowelSyndromeMarica A. Lazo
    • 32. Irritable Bowel Syndrome• A functional bowel disorder characterized by abdominal pain or discomfort and altered bowel habits in the absence of detectable structural abnormalities• 10-20% of adults and adolescents have symptoms c/w IBS, with FEMALE predominance (2-3x as often as men)• Commonly first symptoms occur before age 45
    • 33. Diagnostic Criteria for IBS(ROME II Criteria)
    • 34. Clinical Features• Abdominal pain/discomfort • Prerequisite clinical feature of IBS • Variable in intensity and location • Exacerbated by eating or emotional stress and improved by passage of flatus or stools• Altered bowel habits • Most consistent clinical feature in IBS • Constipation alternating with diarrhea, usually with one symptom predominating
    • 35. Clinical Features• Gas and flatulence • Impaired transit and tolerance of intestinal gas loads • Reflux gas from distal to proximal intestine - flatulence• Upper GI symptoms • 25-50% of patients complain of dyspepsia, heartburn, nausea or vomiting
    • 36. Pathophysiology1. Gastrointestinal motor abnormalities • Increased rectosigmoid motor activity for up to 3 hours after eating • Recordings from the transverse, descending and sigmoid colon showed that the motility index and peak amplitude of high-amplitude propagating contractions (HAPCs) in IBS-D were increased
    • 37. Pathophysiology2. Visceral hypersensitivity • Exaggerated sensory responses to visceral stimulation • Proposed mechanisms: • End-organ sensitivity • CNS modulation • Long-term hyperalgesia • Tonic cortical regulation • Neuroplasticity
    • 38. Pathophysiology3. Central Neural Dysregulation • Clinical association of emotional disorders and stress with symptom exacerbation and the therapeutic response • In response to distal colonic stimulation, the mid-cingulate cortex shows greater activation in IBS patients • Preferential activation of the prefrontal lobe  increased perception of visceral pain
    • 39. Pathophysiology4. Abnormal Psychological Features • Abnormal psychiatric features are present in up to 80% of IBS patients • An association between prior sexual or physical abuse and development of IBS has been reported • Increased motor reactivity of the colon and small bowel to a variety of stimuli and altered visceral sensation associated with lowered sensation thresholds
    • 40. Therapeutic Targets for IBS
    • 41. Pathophysiology5. Post-Infectious IBS • Occurs more commonly in females and affects younger rather than older patients • Risk factors: prolonged duration of initial illness, toxicity of bacterial strain, smoking, mucosal markers of inflammation, female gender, depression, hypochondriasis, and adverse-life events in the preceding 3 months • Campylobacter, Salmonella and Shigella
    • 42. Pathophysiology6. Immune Activation and Mucosal Inflammation • Activated lymphocytes, mast cells, and enhanced expression of proinflammatory cytokines  abnormal epithelial secretion and visceral hypersensitivity • Psychological stress  release of proinflammatory cytokine  alter intestinal permeability
    • 43. Pathophysiology7. Altered Gut Flora • High prevalence of small intestinal bacterial overgrowth in IBS patients (positive lactulose hydrogen breath test) • Bacterial genera with Lactobacillus sequence appear to be absent from IBS, and Collinsella sequences were reduced
    • 44. Pathophysiology8. Abnormal Serotonin Pathways • 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 • Increased release of serotonin may contribute to postprandial symptoms and provides a rationale for the use of serotonin antagonists in the treatment of IBS
    • 45. Approach to the Patient with IBS IBS NOT IBS• recurrence of lower • appearance of the disorder abdominal pain with for the first time in old age altered bowel habits over a • progressive course from time period of time without of onset, persistent diarrhea progressive deterioration after a 48-h fast• onset of symptoms during • presence of nocturnal periods of stress diarrhea or steatorrheal• absence of other systemic stools symptoms such as fever and weight loss• small-volume stool without any evidence of blood
    • 46. Differentials• Lactase deficiency • Diverticular disease of• Celiac sprue the colon,• Side-effects from inflammatory bowel anticholinergic, disease antihypertensive, and • Giardia antidepressant meds • Laxative abuse• Biliary tract disease, • Hyperthyroidism intestinal ischemia, peptic ulcer disorders, and carcinoma of the stomach and pancreas
    • 47. Approach to the Patient with IBS• Young pxs with mild symptoms require minimal diagnostic evaluation, while older pxs or those with rapidly progressive symptoms should undergo a more thorough one• CBC and sigmoidoscopic examination, stool exam• In pxs with persistent diarrhea not responding to anti-diarrhea agents, a sigmoid colon biopsy should be performed to rule out microscopic colitis
    • 48. Approach to the Patient with IBS• In those aged >40 years, an air-contrast barium enema or colonoscopy should also be performed• If the main symptoms are diarrhea and increased gas, the possibility of lactase deficiency should be ruled out with a hydrogen breath test or with evaluation after a 3-week lactose-free diet• Lab features that argue against IBS include anemia, elevated ESR, presence of leukocytes or blood in stool, and stool volume >200–300 mL/d
    • 49. Treatment• High-fiber diet• Anticholinergic drugs inhibit gastrocolic reflex (ipratropium bromide)• Anti-diarrheals (loperamide)• Anti-depressants – TCAs and SSRIs (fluoxetine)• Activated charcoal as part of anti-flatulence therapy• Serotonin Receptor Agonist and Antagonists – alosetron, tegaserod• Chloride Channel Activators – lubiprostone
    • 50. Thank you!