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A. Epidemiology [3]navigator

  1. Prevalence is 8-15 per 1000 persons
  2. Increasing incidence over past 30 years
  3. Incidence 160-220 per 100,000 per year
  4. Highest incidence in Northern areas
  5. Whites > Blacks > Asians and Hispanics

B. Etiology [4,5] navigator

  1. Autoimmune inflammatory disease
    1. Both innate and adaptive immune systems involved
    2. Interactions with colonic epithelium critical
    3. Epithelium, particular in intestine with bacterial load, produce cytokines
  2. Abnormal T cell regulation, abnormal lymphokine responses
    1. Some imbalance in favor of Th2 biased cytokines, mainly IL5 (but not IL4)
    2. Suboptimal response of humans to TNFa inhibition, a Th1 cytokine
    3. Reduced levels of interferon gamma
    4. Abnormal lymphocytes in gut traffic to many other organs
  3. Production of inflammatory Mediators
    1. Particularly leukotrienes (LT) and cytokines
    2. Leukotriene B4 (LTB4) is highly elevated in UC colons
    3. Therapy aimed at blocking LT synthesis appears effective in early trials
    4. ZRatio of interleukin 1 to its receptor antagonist (blocker, IL1-RA) is elevated
    5. High local levels of TNF alpha have been found
  4. Serum Antibody (Ab) Patterns [6]
    1. UC is typically anti-Saccharomyces cerivisiae Ab (ASCA) negative
    2. About 50% of UC patients have periplasmic antineutrophil cytoplasmic Abs (ANCA)
    3. Sensitivity and specificity of ASCA-/pANCA+ for UC are 50% and 97% respectively
  5. Genetics [7]
    1. Low concordance in monozygotic twins (~10%) suggests environmental factors more important than genetic factors
    2. However, 10X increased risk of UC in first degree relatives of UC patients
    3. Increased risk with HLA-DRB1 alleles
    4. Multiple disease susceptibility loci located on chromosomes 3, 7, 12
  6. Microbial factors in highest concentrations in colon are probably the most important contributing environmental factor

C. Presentationnavigator

  1. Presents with (secretory) diarrhea, hematochezia, little pain, tenesmus
  2. Typically with sudden onset of symptoms
  3. Begins in colon at mucocutaneous line (dentate line) at ano-rectal junction
  4. Proximal progression with no skip areas
  5. Overall Involvement:
    1. Left sided colitis ~50%
    2. Pancolitis ~20%
    3. Proctitis ~30%
  6. Numerous extra-colonic manifestations
  7. Frequency of exacerbations is reduced in smokers

D. Intracolonic Symptomsnavigator

  1. Colon Adenocarcinoma
    1. Risk related to extent and duration of disease
    2. Risk not related to severity of disease
    3. Risk of colon cancer may be decreased in UC patients with UC taking medications
    4. Risk increases in UC patients after 10 years of disease
    5. Prior to aggressive treatment, colon cancer risk was >40% at 24 years
    6. Frequent colonoscopy with biopsies is recommended for surveillance
  2. Obstruction
  3. Leakage - perforation
  4. Iron deficiency - hemorrhage
  5. Toxic Megacolon (see below) [8]
  6. Inanition
  7. Strictures, Fistulas (rare in UC), perirectal abscess
  8. Mnemonic is "COLITIS"

E. Extracolonic Symptomsnavigator

  1. Urinary Calculi - oxalate stones
  2. Sclerosing Cholangitis [9]
    1. Predominant liver disease in occurs in ~5% of UC patients
    2. ~80% of patients with primary sclerosing cholangitis eventually develop IBD
    3. Course of disease does not parallel UC and can occur following cholectomy
  3. Cholelithiasis
  4. Erythema nodosum
    1. Course parallels that of active inflammation in UC
    2. Pyoderma gangrenosum may also occur
  5. Retardation of growth
  6. Arthropathy [9]
    1. Occurs in ~30% of cases of UC
    2. Type 1: Distal polyarthritis similar to reactive arthritis, parallels course of UC
    3. Type 2: Proximal arthritis associated usually in HLA-B27+ patients
    4. Type 2 arthritis disease course does not parallel course of UC
    5. Incidence of true ankylosing spondylitis is elevated in IBD (B27+)
  7. Thrombophlebitis
  8. Iatrogenic
    1. Glucocorticoids, immunosuppressive agents
    2. Blood and blood product transfusions
    3. Surgical and/or endoscopic operations
  9. Vitamin Deficiency (Malabsorption)
  10. Eyes
    1. Uveitis, chorioretinitis, iridocyclitis, episcleritis
    2. Anterior uveitis flares parallel UC disease activity in gut
  11. Mnemonic is "ULCERATIVE"
  12. Coombs' Positive Hemolytic Anemia in 0.5-2% [10]

F. Patternsnavigator

  1. Anatomic Locations
    1. Proctitis only
    2. Left sided - sigmoid colitis ± left sided colitis
    3. Pancolitis
  2. Timing
    1. 70% Chronic Relapsing
    2. 20% Chronic Continuous
    3. 10% Fulminant Colitis - includes toxic megacolon: nerve destruction leading to colonic distension with sepsis
  3. Triggers of Disease Flares [11]
    1. Infection - viral upper respiratory infection most commonly, CMV, bacterial, other [26]
    2. Diet - excess fructose and sorbitol intake
    3. Disease progression - new extracolonic manifestations
    4. Antibiotics inducing Clostridium difficile outgrowth
    5. Nonadherence - patient stops or tapers medication
    6. Drug interactions - 5-ASA and mercaptopurine, cholestyramine blocking drug absorption

G. Differential Diagnosis: Enteritis and Colitis [1] navigator

  1. Infectious
    1. Bacterial: Campylobacter, Salmonella, Shigella, Escherichia coli, Yersinia (especially Crohn's)
    2. Antibiotic Associated: Colstridium difficile
    3. Mycobacterial: M. tuberculosis, atypical mycobacteria
    4. Unusual: gonococci, Chlamydia trachomatis
    5. Parasitic: Entameba, Cryptospora, Trichuris, strongyloides
    6. Fungal: Candida, Aspirgillus
    7. Viral: cytomegalovirus (CMV), Epstein-Barr Virus (EBV) [26]
  2. Non-infectious
    1. Inflammatory: diverticulitis, microscopic colitis (collagenous, lymphocytic)
    2. Eosinophilic gastroenteritis, graft versus host disease, radiation related
    3. Behcet's Syndrome, sarcoidosis
    4. Toxic: postoperative diversion colitis, bile acid loss, non-steroidal anti-inflammatory drugs
    5. Laxative use or abuse, cancer chemotherapy
    6. Malignancy: colorectal cancer, small bowel cancer, neuroendocrine (carcinoid) tumor, lymphoma, metastatic neoplasms
    7. Vascular: ischemic colitis (mesenteric ischemia), vasculitis

H. Therapeutic Strategy navigator

  1. Treatment divided into acute induction therapy and maintenance of remission
  2. Acute Moderate to Severe Exacerbation
    1. Usually in patients with known disease, now active
    2. Patients are usually made NPO (nothing taken orally) and given intravenous (IV) fluids
    3. Essential to rule out underlying infection, perforation, other pathology
    4. Aminosalicylates for mild to moderate UC remission induction (4-6 weeks)
    5. Aminosalicylates are given orally, rectally, or both
    6. Glucocorticoids are mainstay of remission induction in severe UC or resistant disease
    7. Oral prednisone or IV methylprednisolone 40mg daily or bid with slow taper is used
    8. Infliximab (Remicade®) can induce remissions in moderate to severe UC [12]
    9. Cyclosporin 2mg/kg IV induces remission in ~70% of glucocorticoid-refractory UC
    10. Cyclosporin 4mg/kg is of no benefit over 2mg/kg in severe UC [13]
    11. Metronidazole ± other antibiotics may be given if infection is suspected
    12. Parenteral nutrition may be required (institute within 2-3 days of NPO)
  3. Chronic Therapy (Remission Maintenance)
    1. Agents based on 5-aminosalicylate are the mainstay of remission maintenance
    2. Maximal doses should be used in moderate and severe UC
    3. Azathioprine or 6-mercaptopurine (6-MP) are used to maintain remissions in moderate and severe UC and alleviate dependence on glucocorticoids
    4. Methotrexate is not effective for maintenance in UC (but is effective in CD) [14]
    5. Mycophenolate (CellCept®) is not as effective as azathioprine in UC maintenance
    6. Metronidazole (or ciprofloxacin) is effective in CD ileitis but not in UC
    7. Low dose glucocorticoids are not recommended for chronic therapy
    8. Infliximab as inducation and maintenance effective 54 weeks after initiation [12]
    9. Avoid overtreatment of "irritable" bowel symptoms such as bloating with increase in anti-inflammatory drugs [15]
  4. Severe Refractory Disease [7]
    1. Proctocolectomy has been the standard for severe glucocorticoid refractory disease
    2. Risk of chronic pouchitis in these patients is high
    3. Probiotics appears to be effective in preventing pouchitis

I. Specific Agents navigator

  1. Sulfasalazine (Azulfidine®)
    1. Remitting, maintenance agent of choice in tolerant patients
    2. Fairly high incidence of side effects with nausea, rash, pancreatitis, others
    3. Dose: 500mg bid-tid then increase to maximum 1.5 gm tid (should be titrated to effect)
    4. Requires weeks to see effect
  2. Olsalazine (Dipentum®) [16]
    1. May be more effective than mesalazine in prevention of relapses in UC
    2. Olsalazine 2gm/day has similar efficacy to sulfasalazine
    3. Olsalazine is better tolerated than sulfasalazine in mild-moderate UC
    4. Doses of 2gm/day or more olsalazine is better than placebo
    5. May cause diarrhea (rate may be increased over sulfasalazine)
  3. Mesalamine (oral, Asacol®, Pentasa®, Lialda®; enema and suppositories, Rowasa®) [17]
    1. Effective in maintaining or improving UC (mild-moderate)
    2. Well tolerated in UC but may cause watery diarrhea
    3. Oral dose is 2.4g/d up to 4.8gm/d, should be started low with increase over 1-3 weeks
    4. Asacol® 400mg tablets given as 800mg tid po
    5. Pentasa® 250mg and 500mg tablets given as 1gm qid po
    6. Once daily oral formulation (Lialda®) approved at 2.4-4.8gm qd [18]
    7. Mesalamine 0.8-1.6gm/day reduces exacerbations >50% over a 6 month period
    8. Proctocolitis may respond to Rowasa enamas without requirement for other agents
  4. Balsalazide (Colazal®) [19]
    1. Prodrug of mesalamine
    2. For mild to moderately active UC
    3. Dose is 2.25gm tid
    4. At least as effective as delayed release oral mesalamine
    5. Similar side effects as mesalamine
  5. Glucocorticoids
    1. Budesonide enemas - distal colitis / proctocolitis only (effective to ~28cm)
    2. Inpatient: moderate dose IV such as methylprednisolone 30-50mg iv q8° or drip
    3. Oral glucocorticoids at 60mg/day, with slow taper over weeks
    4. Avoid treatment with systemic gucocorticoids for >3 months [15]
    5. Phosphatidylcholine 500mg qid reduced glucocorticoid use in steroid-refractory UC [25]
  6. 6-Mercaptopurine (6-MP) and Azathioprine (AZA, Imuran®) [14]
    1. Effective for reducing glucocorticoid doses ("steroid sparing agents")
    2. Helps induce and maintain remissions in UC
    3. Reduces remissions in ~65% of patients with chronic refractory UC
    4. Patients should generally be tested for TPMP (thiopurine methyltransferase) levels or genotype prior to initiating therapy [7]
  7. Cyclosporine [1,14]
    1. Effective at moderately high doses in glucocorticoid resistant exacerbations
    2. Reduces requirement for surgical intervention in steroid-resistant exacerbations
    3. Given 4mg/kg IV for acute UC flares and is rapidly effective within 3-7 days
    4. Doses of 2mg/kg IV may be as effective but safer than higher doses
    5. Increased risk of infection
    6. Consider prophylaxis for Pneumocystis in patients on high dose cyclosporine
    7. Generally reserved as bridge therapy to prevent emergent collectomy
    8. Patients may be weaned off of cyclosporine onto azathioprine
  8. Infliximab (Remicade®) [1]
    1. Infliximab is a chimeric IgG1 monoclonal antibody which blocks TNFalpha
    2. Infliximab given at weeks 0, 2, 6 then every 8 weeks (5-10mg/dose) incudes and maintains remissions better than placebo
    3. Side effects are generally mild, though increased infection and lymphoma risk
  9. Phosphatidylcholine [25]
    1. May reduce mucosal barrier dysfunction found in UC
    2. Encapsulated in Eudragit-S100 capsules to allow pH-dependent release in distal intestine
    3. Dose is 500mg po qid
    4. Permitted complete glucocorticoid withdrawal in 80% of steroid-refractory UC patients without an exacerbation at 12 weeks, compared with 10% on placebo
    5. Well tolerated, with increase in abdominal bloating
    6. Consider in steroid refractory UC
  10. Ursodiol (Actigal®) [21]
    1. Synthetic bile acid (ursodeoxycholic acid)
    2. Used as part of treatment for sclerosing cholangitis (primary and secondary)
    3. Used in patients with UC and sclerosing cholangitis (SC)
    4. In patients with UC and SC, ursodiol reduced risk of colonic dysplasia and neoplasia by 80%
    5. Studies to determine ursodiol effects in UC without SC are being initiated
  11. Nicotine [20]
    1. Nicotine patch may reduce exacerbations in combination with mesalamine
    2. Nicotine patch had no effect on prevention of UC exacerbations during maintenance
    3. However, activity of patch (22mg/day) was confirmed in active UC
    4. Side effects in most patients included nausea, dizziness, local reactions
    5. Overall, nicotine may provide some benefit in the setting of active UC
  12. Epidermal Growth Factor (EGF) [22]
    1. Potent mitogenic peptide which can stimulate epidermal healing
    2. Studied as 5µg daily enemas (in 100mL) to patients with mild-moderate left sided colitis
    3. Induced remission within 2 weeks in 10 of 12 patients (versus 1 of 12 with control)
    4. Remission benefit retained at 4 and 12 weeks
  13. Anti-alpha4/beta7-Integrin Antibody [23]
    1. Blocks lymphocyte migration into inflamed intestinal tissue
    2. Dose 0.5 - 2.0 mg/kg on days 1 and 29 induced remissions in 33% versus 14% placebo
    3. Very well tolerated
    4. Neutralizing antibodies appear in some patients
    5. Opportunistic infections have not been observed

J. Surgerynavigator

  1. Nearly all cases are performed for medical therapy failures
  2. Some cases are performed to reduce risk of developing colon cancer or for polyps
  3. Many patients may have proctocolectomy with anal anastomosis (continant sphincter)
  4. Stool frequency and C-reactive protein levels correlate strongly with colectomy
  5. Probiotics can reduce risk of chronic pouchitis following proctocolectomy [7]

K. Toxic Megacolon [24]navigator

  1. Occurrance
    1. Most commonly found in patients with IBD, usually UC
    2. Also associated with infections and Kaposi Sarcoma
    3. The incidence is declining due to better treatments, earlier recognition
  2. Defined as colonic dilatation with inflammatory colitis, septic symptoms
    1. Severe inflammation occurs from lumen down to smooth muscle layer
    2. Result is paralysis of colonic smooth muscle
    3. This leads to colonic dilatation
    4. Myenteric plexus nerves are not consistently damaged
    5. Nitric oxide, cytokines, leukotrienes, and proteolytic enzymes all paralyze muscle
  3. Bacterial Infections (all associated with bloody diarrhea)
    1. Clostridium difficle pseudomembranous colitis
    2. Salmonella - typhoid and non-typhoid
    3. Shigella
    4. Campylobacter
    5. Yersinia
  4. Parasitic
    1. Entamoeba histolytica
    2. Cryptosporidium
  5. Viral
    1. Cytomegalovirus colitis
    2. Culture negative colitis
  6. Diagnostic Criteria
    1. Radiographic Evidence of colonic distension
    2. Three of: Fever >38°C (101.5°F), Heart Rate >120/min, WBC >10.5K/µL, anemia
    3. One of: dehydration, altered consciousness, electrolyte imbalance, hypotension
  7. Treatment
    1. Blood cultures should be obtained
    2. Nothing per mouth, insert nasogastric tube or intestinal tube
    3. Reduce severity of colitis with broad spectrum antibiotics
    4. Intensive supportive management
    5. Blood counts, electrolytes, serial abdominal films every 12 hours
    6. Parenteral nutrition is of benefit in Crohns Disease but not in Ulcerative colitis
    7. Prophylaxis for stress ulcers and deep vein thromboses is recommended
    8. Glucocorticoids recommended in IBD toxic megacolon to prevent Addisonian reactions
    9. Medical therapy is effective in ~50% of cases
    10. Surgery may be required after 48-72 hours of distension which is not improving

References navigator

  1. Baumgart DC and Sandborn WJ. 2007. Lancet. 369(9573):1641 abstract
  2. Podolsky DK. 2002. NEJM. 347(6):417 abstract
  3. Baumgart DC and Carding SR. 2007. Lancet. 369(9573):1627 abstract
  4. Blumberg RS and Strober WS. 2001. JAMA. 285(5):643 abstract
  5. Bamias G, Nyce MR, De La Rue SA, Cominelli F. 2005. Ann Intern Med. 143(12):895 abstract
  6. Rutgeerts P and Vermeire S. 2000. Lancet. 356(9248):2117 abstract
  7. Farrell RJ and Peppercorn MA. 2002. Lancet. 359(9303):331 abstract
  8. Benkov KJ and Compton CC. 1999. NEJM. 340(3):215 (Case Record)
  9. Grant AJ, Lalor PF, Salmi M, et al. 2002. Lancet. 359(9301):150 abstract
  10. Oliff IA and Compton CC. 2000. NEJM. 342(10):722 (Case Record)
  11. Greenberger NJ. 2000. Ann Intern Med. 133(7):545 (Synopsis)
  12. Rutgeerts P, Sandborn WJ, Feagan BG, et al. 2005. NEJM. 353(23):2462 abstract
  13. Van Assche G, D'Haens G, Noman M, et al. 2003. Gastroenterology. 125:1025 abstract
  14. Langford CA, Klippel JH, Balow JE, et al. 1998. Ann Intern Med. 129(1):49 abstract
  15. Greenberger NJ and Sharma P. 2004. Ann Intern Med. 141(5):374 abstract
  16. Brzezinski A, Rankin GB, Seidner DL, Lashner BA. 1995. Clev Clin J Med. 62(5):317 abstract
  17. Mesalamine Study Group. 1996. Ann Intern Med. 124(2):204 abstract
  18. Mesalamine. 2007. Med Let. 49(1257):25 abstract
  19. Balsalazide. 2001. Med Let. 43(1109):62 abstract
  20. Sandborn WJ, Tremaine WJ, Offord KP, et al. 1997. Ann Intern Med. 126(5):364 abstract
  21. Tung BY, Emond MJ, Haggitt RC, et al. 2001. Ann Intern Med. 134(2):89 abstract
  22. Sinha A, Nightingale JMD, West KP, et al. 2003. NEJM. 349(4):350 abstract
  23. Feagan BG, Greenberg GR, Wild G, et al. 2005. NEJM. 352(24):2499 abstract
  24. Sheth SG and LaMont JT. 1998. Lancet. 351(9101):509 abstract
  25. Stremmel W, Ehealt R, Autschbach F, Karner M. 2007. Ann Intern Med. 147(9):603 abstract
  26. Babyatsky MW, Keroack MD, Blake MA, et al. 2007. NEJM. 357(20):2068 (Case Record) abstract