8. Ulcerative Colitis
• Inflammatory reaction involving primarily
colonic mucosa
• Colon appears ulcerated, hyperemic
• Inflammation is uniform and continuous, with
no intervening areas of normal mucosa.
• Rectum usually involved (95%) and extends
proximally
9. UC Clinical Features
• Major symptoms:
– Bloody diarrhea/constipation
– Abdominal pain
– Weight loss
– Fever
10. UC Manifestations/Complications
• Physical findings (nonspecific)
– Tenderness along colon
• Extracolonic manifestations
– Anemia of chronic disease + Fe deficiency
– Leukocytosis, left shift
– Electrolyte abnormalities
– Hypoalbuminemia
• Colon CA
• Toxic megacolon
• Hemorrhage
11. UC Clinical Course
• > 50% will relapse within 1 year (may be
prolonged remissions)
• Severity of symptoms reflects intensity of
inflammation
• Rectal involvement-major symptoms rectal
bleeding, tenesmus
• 85% have mild to moderate disease
• 15% disease involves entire colon
12. UC Characteristic Appearance of Colon
• Smooth “lead pipe” appearance
radiographically
• “Pseudopolyps”: Inflammatory, not neoplastic
resulting from regenerating mucosa
surrounded by ulceration
• Dysplasia may influence decision for
colectomy
13. Crohn's Disease
• Inflammation extending through all layers of
intestinal wall
• Involves entire digestive tract, especially distal
ileum, colon, anorectal area
14. Crohn's Disease Clinical Presentation
• (Depends on anatomic location of disease)
• Fever
• Abdominal pain (with colonic involvement)
• Diarrhea often w/blood (with colonic
involvement)
• Generalized fatigability
• Weight loss
15. Crohn's Disease Bowel Appearance
• Bowel appears greatly thickened, lumen
narrows (associated with varying degrees of
obstruction.)
• Mucosa appearance variable; may appear
normal, in contrast to UC
• "Cobblestone" appearance of mucosa
• Discontinuous "skip lesions" present
• Rectum spared in 50% of cases (never in UC)
16. Crohn's Disease Complications
• Severe complications include fistulas, fissures,
abscesses
• Toxic megacolon: less than with UC
• Colonic cancer: less than with UC
17. Systemic Complications of IBD
• Joint manifestations (25% incidence)
• Arthralgias to acute arthritis
• Skin manifestations (15% incidence)
• Severity reflects activity of bowel disease
• More common with colonic disease
• Erythema nodosum: and eruption of painful red nodules
of legs
• Pyoderma gangrenosum: ulcerating lesion often
occurring on the trunk
• Aphthous ulcers: resemble canker sores of mouth
• Treat symptomatically only
18. Systemic Complications of IBD
• Ocular manifestations (5% incidence)
• May represent severe manifestation of
disease
• Episcleritis, recurrent iritis may occur
• Activity parallels course of bowel disease
• Lesion may respond when colectomy
performed
20. Treatment of UC and Crohn's Disease
• Similarities: Initial treatment is medical
• Surgery reserved for specific complications,
intractable disease
• Differences: Response to drug therapy may
differ
• Complications often different
• Prognosis following surgery different
21. Goals of Pharmacotherapy for IBD
• Control inflammatory process
• Replace nutritional losses
• Improvements following IV fluid and
electrolyte replacement
• Blood transfusions may be necessary
• Agents to control diarrhea should be used
with caution
22. Drug Therapy in IBD
• Aminosalicylates
• Sulfasalazine-reaches colon intact where diazo
bond is cleaved by flora to mesalamine
(active) and sulfapyridine.
• Proposed mechanisms of action:
– Inhibit NKC's
– Inhibit cyclooxygenase and lipoxygenase pathways
– Repair neutrophil function
– Scavenge oxygen radicals
23. Problems with sulfasalazine
• Many patients allergic or intolerant
(sulfapyridine portion)
• May be possible to "desensitize" patients
• Other adverse effects:
– fever, rash, hepatic dysfunction, agranulocytosis,
hemolytic anemia, thrombocytopenia,
pancreatitis, adverse sperm effects in males
24. • Corticosteroids:
– exact mechanism unknown
• Enemas:
– Decrease tenesmus by suppressing rectal inflammation
• IV:
– appropriate in severely ill patients to avoid uncertainty of
oral absorption
• PO:
– After 7-10 days, if improvement (dec. fever, diarrhea,
increased appetite), start oral feedings and taper steroids
• To decrease side effects: Use rapid tapering
schedules
• Every other day schedules
• AM dosing
26. • Azathiaprine-Discouraging results
• 6-Mercaptopurine-Active metabolite of azathiaprine
• Role in refractory Crohn's
– Studies have shown reductions in steroid use, healing of
fistulas and abscesses.
• Toxicities: pancreatitis 3.3%
• BM suppression 2%
• Allergy 2%
• Hepatitis 0.3%
• Should be considered in treatment of patients with
refractory Crohn's, or in patients intolerant of
steroids or sulfasalazine
27. Methotrexate in IBD
• Interferes with IL-1's inflammatory actions
• Study results:
– In patients with refractory IBD, given MTX 25 mg
IM weekly x12 weeks, then oral taper:
– 5/7 with UC, 11/14 Crohn's improved allowing
decreased steroid doses
28. Cyclosporine in IBD
• Study results:
– In patients with resistant Crohn's, cyclosporine 5-
7.5 mg /kg/d x3 months
– 59% cyclosporine vs 32% placebo showed
improvement.
– No long term improvement
– Side effects need to be assessed (renal
impairment)
29. Antibiotics in IBD
• Role:
– As treatment for intercurrent infections
– As primary treatment for IBD
• Considerations:
– Infections can cause flares in IBD
– C. jejuni infections can mimic IBD
• Uncontrolled study:
– Continuous treatment with ATB's resulted in
symptomatic improvement in 41/44 patients with
Crohn's
30. Metronidazole in IBD
• Only antimicrobial with firm rationale for use
in Crohn's
• May work through mechanism independent of
antimicrobial properties
• No evidence in UC, except in treating C.dif
infections
• Study results:
– Patients with unremitting Crohn's, 21/21 had
improvements in drainage, erythema, induration.
10/18 had complete healing.
31. Anticholinergics/Antispasmodics
• Symptomatic treatment
• Use should be discouraged in acute
symptoms;
• May ppt. ileus, toxic megacolon
• Major usefulness:
– control of diarrhea in patients with well
established, chronic symptoms
32. Prognosis for IBD
• UC:
– 20-25% will require colectomy
– Indication for colectomy:
• failure to respond to medical management
– Long term prognosis- variable
– 10 year mortality for severe first attacks=5-10%
– 75% relapse rate
33. Prognosis for IBD
• Crohn's:
– prognosis less favorable than for UC
– disease responds less favorably to medical
therapy
– 2/3 develop complications requiring surgery
– mortality increases with duration of disease (5-
10%)
– surgery not a primary form of therapy-high rate of
recurrence
122. ETIOLOGIC HYPOTHESES
There are four widely accepted etiologic hypotheses for these idiopathic disorders. Each of these hypotheses involve microbial agents. The simplest and most amenable to curative treatment is that a viable pathogen persistently infects the intestine. The most widely studied pathogen is Mycobacterium paratuberculosis which causes naturally occurring Johne’s disease, a chronic progressive granulomatous enterocolitis in ruminants (cattle, sheep, goats and deer). Intestinal Helicobacter species (non H. pylori species) can cause colitis in immunodeficient mice and some genetically engineered mice, including those with IL-10 deficiency, but have not been implicated in human disease. Measles, mumps and Listeria have their advocates, but have not been widely reproduced. Similarly, toxigenic E. coli have been isolated from patients with both ulcerative colitis and Crohn’s disease but need to be more thoroughly investigated.
Dysbiosis is an altered balance of protective bacteria (Lactobacillus and Bifidobacterium species) and aggressive commensal organisms (including Bacteroides, Enterococcus, inherent/invasive E. coli).
Defective mucosal integrity could lead to enhanced uptake of commensal luminal bacteria which could then overwhelm the normally protective activities of the mucosal immune system. Decreased barrier function could be a result of altered mucus, increased permeability, decreased epithelial metabolic activity, or impaired mucosal healing after injury.
Dysregulated immune responses to ubiquitous luminal antigens could lead to tissue injury. This dysregulation could be a result of loss of protective responses leading to defective tolerance to luminal antigens, overally aggressive cell mediated immune function or dysregulated apoptosis of macrophages or T lymphocytes.