eMedicine Specialties > Gastroenterology > Colon
Collagenous and Lymphocytic Colitis
Updated: Jul 15, 2009
Introduction
Background
Collagenous colitis (CC) was described concurrently in 1976 by Lindstrom and by Freeman1 . In 1980, Read described microscopic colitis, which is clinically indistinguishable from CC but is differentiated from it by colonic biopsy features. Later, the term lymphocytic colitis (LC) was proposed by Lazenby to replace the term microscopic colitis and to distinguish it from infectious colitis and inflammatory bowel disease (ulcerative colitis and Crohn disease). The term microscopic colitis is now used to describe both CC and LC, and these conditions should be considered in any patient with unexplained nonbloody diarrhea. Patients undergoing either sigmoidoscopy or colonoscopy for unexplained diarrhea who have normal endoscopic findings should have biopsy samples taken to diagnose or rule out either form of microscopic colitis.
LC and CC are relatively rare conditions that are diagnosed when a patient with chronic watery nonbloody diarrhea has an endoscopically or radiographically normal colon, but colonic biopsies show unique inflammatory changes. Because the mucosa is not ulcerated or otherwise disrupted, the diarrhea generally does not contain blood or pus.
Pathophysiology
- The characteristic feature of LC is an infiltration of lymphocytes into the colonic epithelium. CC shares this feature but additionally shows a distinctive thickening of the subepithelial collagen table. LC and CC have been suggested to represent different phases of a single pathophysiologic process, with LC possibly being a precursor or earlier phase of CC; however, this has not been proven.
- The diarrhea in CC is more likely due to the inflammatory process than to the subepithelial collagen layer, although this layer may serve as a cofactor in the role of a diffusion barrier.
- Increased levels of immunoreactive prostaglandin E2 in stool water may contribute to a secretory diarrhea.
- Some patients with CC and concurrent collagenous infiltration of the duodenum and/or the ileum have demonstrated altered small bowel dysfunction, demonstrated by reduced D-xylose absorption.
- Some individuals have bile acid malabsorption demonstrated by the Se-75-homotaurocholate (SeHCAT) test, in which a positive test result is shown by retention of less than 11% of the administered dose of radioactivity after 7 days.
- Some patients with CC may have increased mucosal secretion of vascular endothelial growth factor, a fibrosis-enhancing peptide.
Frequency
United States
True incidence is not known. The disease has been increasingly diagnosed over the past 20 years, but it is still uncommon. A recently published population-based study found the incidence of microscopic colitis to increase significantly from 1.1 per 100,000 persons in the late 1980s to 19.6 per 100,000 persons by the end of 2001. Rates increased with age. Prevalence at the end of the study period was 103.0 per 100,000 persons (39.3 for CC and 63.7 for LC).
Mortality/Morbidity
Morbidity is limited to the consequences of diarrhea and malabsorption, including metabolic abnormalities such as hypokalemia and dehydration, weight loss, fatigue, and vitamin deficiencies. This is not considered a life-threatening condition; however, profuse watery diarrhea may lead to severe dehydration and electrolyte abnormalities requiring intensive resuscitation.
Sex
LC affects similar numbers of men and women, while CC is up to 20 times more frequent in women than in men.
Age
Both conditions are observed most commonly in people older than 40 years, with peak incidence in the sixth and seventh decades of life, and the incidence of both conditions increases with age. Isolated cases have been reported in younger populations, including children.
Clinical
History
- A protracted course of nonbloody diarrhea occurs. Diarrhea may be of high volume; some patients may eliminate more than 1500 mL of fluid per day.
- Symptoms may have been present from several months to 2-3 years before medical attention is sought and a diagnosis is made. In fact, perhaps half of patients proven to have microscopic colitis meet the Rome, Rome II, and Manning symptom-based criteria for diarrhea-predominant irritable bowel syndrome and may be so misdiagnosed until endoscopic biopsies of the colon are taken.
- Less frequent complaints include abdominal cramping, fecal incontinence, and weight loss, although weight loss may be seen in 40% or more of patients with CC.
- Incontinence is probably more a reflection of the advanced age of those individuals who are affected, and patients with this problem may do well if treated with antidiarrheal agents.
Physical
- Physical examination usually does not reflect specific abnormalities.
- Severely affected individuals may show signs of dehydration, malnutrition, and weight loss.
Causes
No definite etiology has been determined, but evidence now indicates that drug consumption may trigger underlying inflammatory factors in the colons of affected individuals, while others may exacerbate the diarrhea in patients with idiopathic microscopic colitis. While many drugs, either alone or in combination, may cause diarrhea as an adverse effect, nonsteroidal anti-inflammatory drugs (NSAIDs) show a strong trend (p=0.057) toward increasing the risk of CC, with rechallenge having been shown to cause recurrence of CC. Antidepressant selective serotonin reuptake inhibitors (SSRIs) as a group increase the risk of CC, but, among this class of medications, sertraline alone significantly increases the risk of LC. Anecdotal reports of of a large number of additional drugs have been associated with the onset of the microscopic colitides. Among these, ranitidine (confirmed by rechallenge), aspirin, acarbose, ticlopidine, and proton pump inhibitors have high-level evidence ofcausality,whileflutamide, simvastatin, carbamazepine and lisinopril have intermediate-level evidence.
- Some patients have had histologic findings consistent with both CC and LC at different points during the course of disease. This raises the possibility that these may be different manifestations of the same medical condition or different points along a continuum.
- Many case reports describe patients with preexisting presumed autoimmune conditions, such as celiac sprue, psoriasis and rheumatoid arthritis, who subsequently are diagnosed with microscopic colitis. Patients diagnosed with LC also have had uveitis, idiopathic pulmonary fibrosis, juvenile diabetes mellitus, pernicious anemia, autoimmune thyroid disease, and idiopathic thrombocytopenic purpura. Approximately 1/3 of patients with celiac disease have histologic findings consistent with microscopic colitis. For this reason microscopic colitis should be considered in patients diagnosed with celiac disease who have diarrhea that fails to respond to a gluten-free diet. Removal of gluten from the diet, however, is ineffective in treating microscopic colitis in the absence of celiac disease.
- Microscopic colitis and inflammatory bowel disease (Crohn's disease or ulcerative colitis) have been diagnosed concurrently or sequentially in a small number of cases, with either diagnosis preceding the other. The two conditions may have similar histologic features, making the distinction between them difficult.
- LC was diagnosed in a patient who failed to respond to antibiotic therapy for diarrhea associated with Campylobacter jejuni infection in the stool. The infection theoretically might have stimulated an autoimmune response that resulted in LC.
- Increased mast cells in some LC patients might indicate that degranulation products could serve as a chemoattractant for inflammatory cells.
- While only 14% of patients with LC were smoking actively when diagnosed, 23% were former smokers, suggesting that smoking may actually be protective against the development of LC. Excessive production of nitric oxide by inducible nitric oxide synthase (iNOS) may result in cytotoxicity through the generation of peroxynitrite that is formed when nitric oxide reacts with superoxide. Corticosteroids inhibit iNOS biosynthesis in some cells, and newer inhibitors of this enzyme may have a future role in the management of LC and other forms of colitis. Nitric oxide diffuses into cells and can induce inflammatory cell damage by causing nitration reactions. Increased nitric oxide generation has been reported in CC. The absence of nitrotyrosine staining, which is an indicator of active inflammation typically seen in ulcerative colitis, may correspond to the lesser degree of inflammation in CC compared with ulcerative colitis.
- Diarrhea associated with CC has been proven to be due to reduced net Na+ and Cl- absorption, with the thickened collagen layer serving as a diffusion barrier. The epithelium nearly completely loses its ability to absorb these ions. In fact, the shift in net chloride flux is to secretion rather than absorption.
- Secretion of vascular endothelial growth factor, a fibrosis-enhancing peptide, is noted to be increased by the mucosa in some patients with CC. This may play a part in the pathogenesis.
Differential Diagnoses
| Celiac Sprue | Irritable Bowel Syndrome |
| Crohn Disease | Ulcerative Colitis |
| Giardiasis | |
| Hyperthyroidism | |
| Inflammatory Bowel Disease |
Other Problems to Be Considered
Infectious colitis (other than Clostridium difficile infection)
Ischemic colitis
Laxative abuse
Workup
Laboratory Studies
- Blood studies
- Results usually are within the reference range, but anemia, hypokalemia, hypoalbuminemia, elevation of the erythrocyte sedimentation rate, or a combination of these findings may be present.
- HLA-A1 is more frequent in patients with LC (67%) than in controls (28%) or in patients with CC (26%).
- HLA-B3 has not been reported in patients with LC. A frequency of 26% is expected in controls and also is observed in patients with CC.
- The HLA patterns observed in other gastrointestinal conditions, such as Crohn disease, have not been found in LC.
- Approximately 50% of both patients with CC and patients with LC may have circulating autoantibodies, especially antiparietal cell, antithyroglobulin, and antimicrosomal antibodies.
- Stool studies
- Some affected patients have a diminished ability to absorb water resulting from reduced colonic absorption of sodium and chloride. Chloride/bicarbonate exchange across the colonic mucosa also may be reduced.
- Stool evaluation on occasion may show the presence of leukocytes. In these circumstances, the stool should be tested for enteric bacterial pathogens, ova and parasites, and C difficile.
- A prolonged (24- to 72-h) stool collection occasionally may demonstrate steatorrhea in affected individuals. A finding of greater than 7 g of fecal fat excretion per 24 hours in an individual ingesting 100 g of fat per day usually is indicative of fat malabsorption, and, even if microscopic colitis is present, a diagnosis of concurrent sprue should be considered.
Imaging Studies
- Findings on plain abdominal radiograph, barium enemas, and CT scans typically are normal or nonspecific and show no evidence of colonic mucosal damage or wall abnormality.
Other Tests
- Immunohistochemical studies of biopsies in LC and CC cases demonstrate abnormalities consistent with a mixed histocompatibility-restricted mechanism.
- The excessive intraepithelial lymphocytes observed in LC are predominantly CD4+ T cells rather than CD8+.
Procedures
- Biopsies obtained by sigmoidoscopy or colonoscopy are necessary to diagnose LC or CC.
- If a colonoscopy is performed, biopsies should be taken from the rectosigmoid and possibly also from the right side of the colon. Approximately 95% of patients with microscopic colitis will have diagnostic left colon biopsies; but, if these biopsies are nondiagnostic at sigmoidoscopy in a patient in whom clinical suspicion remains high, total colonoscopy for right-sided biopsies may confirm the diagnosis.
- In individuals with LC or CC, the mucosa appears normal endoscopically or occasionally mild mucosal edema may be seen. It does not show the more readily apparent changes of inflammatory bowel disease such as friability, ulceration, and pseudopolyps. Most patients have similar degrees of histologic abnormality in the right and left sides of the colon.
Histologic Findings
- Surface epithelium shows a chronic inflammatory infiltrate of plasma cells, lymphocytes, and eosinophils in the lamina propria.
- Intraepithelial lymphocytosis, with greater than 20 lymphocytes per 100 epithelial cells, is pathognomonic of the diagnosis of LC (see Media file 1), although lesser numbers of IEL may be present in some patients with LC.
- Epithelial cell damage is demonstrated by cell flattening, subepithelial blebs, and denuded epithelium. Fixed specimens may show epithelial loss and detachment.
- Crypts may have minimal architectural distortion as in Crohn's disease or ulcerative colitis. However, typically, evenly spaced parallel crypts of equal diameter are present.
- CC shares the histologic features of LC but additionally demonstrates a thickened subepithelial collagen layer (usually >10 µm) in the lamina propria, compared to a normal thickness of 5-7 µm.
- For comparison, a representative biopsy of CC is shown in Media file 2.
- In some biopsy specimens, the surface epithelium may be denuded or partially detached from the collagen layer, even simulating pseudomembranes in rare cases. This either may be artifactual or may be due to a defect in adherence to the subepithelial membrane.
Treatment
Medical Care
- Evaluating treatment options is impaired by the fairly frequent occurrence of spontaneous remission of symptoms; however positive placebo-controlled double-blind randomized trials of budesonide have been performed and reported in both LC and CC.
- A trial of dietary restriction and avoidance of potentially aggravating drugs (particularly nonsteroidal anti-inflammatory drugs) may alleviate symptoms in some patients, but many will require medical therapy.
- Treatment should be initiated with the least toxic regimen or medication, with stronger medication used only if milder treatment fails. Generally, 4-6 weeks should be allowed before deeming a particular medication ineffective in the treatment of CC or LC.
- One possible treatment algorithm is as follows:
- First line: Loperamide (Imodium AD) or diphoxylate/atropine (Lomotil) for mild diarrhea.
- Second line: Bismuth subsalicylate, two or three 262 mg tab tid or qid for 1-2 months (effective in up to 90% of patients); mesalamine, 3 g/d for 8 wk; or cholestyramine (especially if bile acid malabsorption is documented), at a mean dose of 8 g/d in moderate disease.
- Third line: If patient is still not responding or if a patient has clinically more severe colitis, a 6-week course of budesonide at the lowest effective dosage (usually 9 mg each morning) or a 2-week course of high-dose prednisone (60-80 mg/d) before tapering can be prescribed. Longer courses of budesonide may be beneficial, and, while systemic adverse effects may occur, little or no adrenal suppression should be anticipated. Recurrences after discontinuation of budesonide usually respond to reinstitution of this same medication. Longer courses of prednisone (up to 2 mo before tapering) may be needed in some patients, but recurrence is common after its discontinuation. In a randomized, double-blind, placebo-controlled study, Miehlke et al evaluated treatment of lymphocytic colitis with oral budesonide.2 At week 6, remission was documented by colonoscopy and histology in 86% of the budesonide group compared with 48% of those administered placebo (P = 0.01). Histologic remission was confirmed in 73% of those receiving budesonide and 31% of patients administered placebo (P = 0.03).2 Relapse during follow-up was evident in about 44% (15 patients), but 8 of those who had a relapse again had a response to budesonide. Clinical remission and improved histology is achieved in a majority of patients with lymphocytic colitis when treated with budesonide.2
- Fourth line: Some refractory cases may benefit from azathioprine (approximately 2 g/kg/d) or 6-mercaptopurine, but responses often take months to occur. Methotrexate can alternatively be used in this setting.
- Patients who respond to treatment, but experience a recurrence, will often respond again to the same previously effective medication.
Surgical Care
If colitis is refractory to continued medical therapy or if effective medication cannot be tolerated, colectomy or ileostomy might be the only effective therapy; however, this seldom is necessary.
Consultations
Consultation with a gastroenterologist often is needed to make the diagnosis and to work through the treatment algorithm.
Diet
- Patients should avoid or eliminate possible secretagogues, such as caffeine, and, when appropriate, lactose-containing products.
- A low-fat diet is advisable if steatorrhea is documented.
Medication
Medication is indicated only if discontinuing dietary components or medications considered possibly responsible for the illness fails to alleviate the symptoms. As above, treatment is initiated with the least toxic effective agents. If a patient fails to respond to simple antidiarrheal drugs, anti-inflammatory or immunosuppressive medications may be required. Studies of budesonide in LC have shown an 86% response rate in symptoms and in histologic findings, with an 81% response rate in CC. A treatment algorithm is discussed above.
Antidiarrheal agents
Appropriate in mild cases.
Loperamide hydrochloride (Imodium AD)
Poorly absorbable opiate that decreases colonic smooth muscle contraction and propulsive activity. Slows intestinal motility and delays colonic transit. Reduction of gastrointestinal secretion may contribute to the antidiarrheal effect. Well-tolerated and safe drug when taken in recommended dosages.
Dosing
Adult
Chronic diarrhea conditions: 2 mg (1 cap or 10 cc elixir) PO after each loose bowel movement; not to exceed 16 mg/d
Pediatric
<2 years: Not established
2-5 years: 1 tsp PO after first loose bowel movement, followed by 1 tsp after each subsequent loose bowel movement; not to exceed 3 tsp/d
6-8 years: 2 tsp or 1 cap after first loose bowel movement, followed by 1 tsp or one half cap PO after each subsequent loose bowel movement; not to exceed 4 tsp or 2 cap per d
9-12 years: 2 tsp or 1 cap PO after first loose bowel movement, followed by 1 tsp or one half cap PO after each subsequent loose bowel movement; not to exceed 6 tsp or 3 cap per d
>12 years: Administer as in adults
Interactions
Phenothiazines, tricyclic antidepressants, and CNS depressants may increase loperamide toxicity
Contraindications
Documented hypersensitivity; high fever (temperature >101°C); blood or mucus in stools
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Concurrent antibiotic therapy; pregnancy; in case of accidental overdose, seek professional assistance or contact poison control center immediately; discontinue use if no clinical improvement in 48 h; because loperamide primarily is metabolized in liver, monitor for CNS toxicity in patients with hepatic insufficiency; do not use medication if high fever or blood in stool coincides with diarrhea
Diphenoxylate hydrochloride/atropine sulfate (Lomotil)
Antidiarrheal agent chemically related to narcotic analgesic meperidine. A subtherapeutic dose of anticholinergic atropine sulfate is added to discourage overdosage, in which case diphenoxylate may clinically mimic the effects of codeine.
Each tab of Lomotil (or 5 cc of elixir) contains 2.5 mg diphenoxylate hydrochloride and 0.025 mg atropine sulfate.
Dosing
Adult
2 cap (or 10 cc elixir) PO qid until symptoms are under control; then use smallest effective dose
Pediatric
<2 years: Not recommended
<12 years: Use liquid Lomotil; do not use tab
Initial: 0.3-0.4 mg/kg PO qd divided qid; adjust dose downward according to overall nutritional status and degree of dehydration
>12 years: Administer as in adults
Interactions
Lomotil may delay metabolism of drugs in liver; CNS depressants, MAOIs, and antimuscarinic agents may increase the toxicity of this drug combination
Contraindications
Documented hypersensitivity; diarrhea caused by C difficile or other enterotoxin-producing bacterial pathogens; obstructive jaundice
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Overdosage may result in severe respiratory depression; carefully monitor and maintain fluid and electrolyte levels; because a subtherapeutic dose of atropine has been added to diphenoxylate hydrochloride, consider precautions relating to atropine; caution patient regarding activities requiring mental alertness, such as driving or operating dangerous machinery; explain potential reactions with concurrent administration of alcohol, barbiturates, or other tranquilizers
Bismuth subsalicylate (Pepto-Bismol)
Controls diarrhea by reducing fluid secretion into intestinal lumen, by binding bacterial toxins, or by acting as an antimicrobial agent.
Dosing
Adult
3 tab PO in morning, 2 tab PO at noon, and 3 tab PO at night for an 8-wk trial
Pediatric
<3 years: Use special caution
3-6 years: One-third tab PO, repeat q0.5-1h prn; not to exceed 8 doses/24 h
6-9 years: Two-thirds tab PO, repeat q0.5-1h prn; not to exceed 8 doses/24 h
9-12 years: 1 tab PO, repeat q0.5-1h prn; not to exceed 8 doses/24 h
>12 years: Administer as in adults
Interactions
Coadministration with anticoagulants may increase risk of bleeding; may increase toxicity of aspirin and hypoglycemics; decreases effects of tetracyclines and uricosurics
Contraindications
Documented hypersensitivity; children with chickenpox and flu; diarrhea with high fever, mucus, or blood is possible contraindication
Precautions
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
May cause temporary and harmless darkening of tongue and/or black stool; alcohol consumption may cause abdominal cramps, nausea, and vomiting; drink plenty of clear fluids to help prevent dehydration
Anion exchange resins
Diarrhea in patients with LC and possible bile salt malabsorption may respond to exchange resins.
Cholestyramine (Questran, LoCholest)
Absorbs bile salts in the intestine, resulting in an insoluble complex that is excreted in feces.
Dosing
Adult
9 g of Questran (1 packet or 1 level scoopful contains 4 g of anhydrous cholestyramine resin) PO qd or bid with fluids initially; not to exceed 6 packets or scoopfuls in a d
Pediatric
Not established
Interactions
Cholestyramine adsorbs many medications; other drugs should be taken at least 1 h before or 6 h after cholestyramine is ingested; because of bile salt adsorption, systemic absorption of dietary fat and fat-soluble vitamins (A, D, E, and K) may be impaired
Contraindications
Documented hypersensitivity; complete biliary obstruction
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution in renal insufficiency or volume depletion; prolonged use may result in vitamin K and folic acid deficiency or hyperchloremic acidosis
Antispasmodics
Some patients with cramping pain associated with diarrhea will respond to antispasmodic medication.
Hyoscyamine (Levsin SL, Levbid, Symax, Cystospaz)
Anticholinergic agent with limited and generally symptomatic utility in patients with colitis. Levsin or Levsin SL (sublingual) is dispensed as 0.125-mg tab, Cystospaz as 0.15-mg tab, and Levbid or Symax as 0.375-mg tabs.
Dosing
Adult
Levsin or Cystospaz: 1-2 tab PO (or SL if using Levsin SL) q4h; not to exceed 12 tab per 24 h
Levbid or Symax: 1 tab q12h
Pediatric
<12 years: Reduce dosage in proportion to age and weight
>12 years: Administer as in adults
Interactions
Cholinergic blockade may occur when used with other antimuscarinics, amantadine, haloperidol, phenothiazine, MAOIs, tricyclic antidepressants, or some antihistamines; antacids may interfere with absorption
Contraindications
Documented hypersensitivity; glaucoma; obstructive uropathy; small or large bowel obstruction; pyloric stenosis; achalasia; paralytic ileus; severe ulcerative colitis; toxic megacolon; myasthenia gravis
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Caution in coronary heart disease; congestive heart failure; arrhythmias; autonomic neuropathy; hyperthyroidism; hypertension; reflux esophagitis
Topical anti-inflammatory drugs
Drugs that reduce inflammatory changes at level of the colonic wall may be needed in subset of colitic patients who fail to respond to antidiarrheal medication.
Sulfasalazine (Azulfidine EN-tabs)
Prodrug complexing the active component of 5-aminosalicylic acid (5-ASA) with an inactive sulfapyridine moiety to prevent systemic absorption in upper gastrointestinal tract. In the colon, the diazo bond is cleaved by bacterial flora and active 5-ASA is released to function as a topical anti-inflammatory drug. Adverse effects typically are due to sulfapyridine rather than to 5-ASA.
Dosing
Adult
Initially: 500-1000 mg PO bid/qid, with ideal dose being lowest effective dose
Dosage reduction may be required with concurrent oral anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants
Pediatric
<2 years: Not established
>2 years:
Initial: 40-60 mg/kg PO qd in 3-6 divided doses
Maintenance: 30 mg/kg PO qd divided qid
Possible dosage reduction required with concurrent oral anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants
Interactions
Effects of oral anticoagulants, sulfonylurea hypoglycemic agents, and hydantoin anticonvulsants can be potentiated by sulfonamides (may need to adjust dose of these medications to avoid toxicity)
Contraindications
Documented hypersensitivity; urinary obstruction
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Do not crush or chew tab; swallow with plenty of water; avoid excessive exposure to sunlight; caution in patients with renal or hepatic impairment and blood dyscrasias
Mesalamine (Asacol, Pentasa)
Controlled-released formulations of 5-ASA and cause fewer side effects than sulfasalazine due to absence of the sulfa moiety. Pentasa is ethylcellulose-coated 5-ASA coated with an acrylic-based resin that dissolves in neutral or alkaline pH found in the terminal ileum or the colon. Dissolution of the coating of these tablets releases active 5-ASA where it can be topically active. These medications are more costly than sulfasalazine but typically better tolerated. Asacol is dispensed in 400-mg tabs. Pentasa is available in 250-mg tab.
Dosing
Adult
Asacol: 400-1200 mg PO tid
Pentasa: 1000 mg PO qid
Pediatric
Not established
Interactions
Decreases effect of iron, digoxin, and folic acid; mesalamine increases effect of oral anticoagulants, methotrexate, and oral hypoglycemic agents
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Usually safe but benefits must outweigh the risks.
Precautions
Impaired hepatic and renal function; can cause acute tolerance syndrome, which may be difficult to distinguish from inflammatory bowel disease; elderly people may have difficulty administering and retaining rectal suppositories; caution in patients with renal or hepatic impairment
Corticosteroids
Systemic anti-inflammatory agents that are readily absorbed from the gastrointestinal tract. Have a multitude of significant side effects when used over a prolonged period of time. Patients who fail to respond adequately to topical anti-inflammatory drugs may benefit from a course of corticosteroid therapy.
Prednisone (Deltasone, Orasone, Sterapred)
Inexpensive corticosteroid available in many strengths, which simplifies tapering schedules. Methylprednisolone (Medrol), dexamethasone (Decadron), or hydrocortisone can be used instead of prednisone. Dosage should be adjusted based on relative potencies.
Dosing
Adult
30-40 mg PO qd for 2 wk to 2 mo, then taper as tolerated
Pediatric
4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve
Interactions
Barbiturates, hydantoin, and rifampin increase metabolism of corticosteroids by induction of hepatic microsomal enzymes; macrolides, oral contraceptive pills, and ketoconazole can potentiate corticosteroid effects; can worsen symptoms of myasthenia gravis; increased risk of gastric ulcerations with concurrent NSAID or aspirin use
Contraindications
Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
Hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; abrupt discontinuation of glucocorticoids may cause adrenal crisis (adrenal insufficiency)
Budesonide (Entocort EC)
Topical glucocorticoid delivered to the small bowel and ascending colon in a time-dependent manner. Active drug is coated with methylcellulose which dissolves at pH of 5.5 or greater, starting in the duodenum. Does not suppress the hypothalamus-pituitary-adrenal axis to a significant degree.
Dosing
Adult
9 mg PO qd for up to 8 wk
Pediatric
Not established
Interactions
Ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin, and other CYP3A4 enzyme inhibitors may significantly increase serum levels of budesonide
Contraindications
Documented hypersensitivity; systemic fungal infections; ileocolostomy during immediate or early postoperative period
Precautions
Pregnancy
C - Safety for use during pregnancy has not been established.
Precautions
If improvement fails to occur within 2-3 wk, discontinue therapy; symptomatic improvement may be misleading and should not be used as sole criterion in judging efficacy (sigmoidoscopic examination and x-ray visualization are essential for adequate monitoring); caution where there is a probability of impending perforation or abscess, pyogenic infections, intestinal anastomoses, obstruction, extensive fistulas and sinus tracts; caution in patients with tuberculosis or other infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer disease, glaucoma or cataracts
Immunosuppressant drugs
Have been administered to small number of patients with LC who have not responded to other medical therapy. Specific indications and recommended dosages have not been established yet.
Azathioprine (Imuran), 6-mercaptopurine (Purinethol)
Azathioprine is an antimetabolite available in tablet form for oral administration or in 100-mg vials for IV injection and is an imidazolyl derivative of 6-mercaptopurine. It is cleaved in vivo to mercaptopurine. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after taken.
Dosing
Adult
Not established; 1 mg/kg/d PO for 6-8 wk suggested, increase by 0.5 mg/kg PO q4wk until response or dose reaches 2.5 mg/kg/d
Need to decrease dose if concurrently taking allopurinol
Pediatric
Initial dose: 2-5 mg/kg/d PO/IV
Maintenance dose: 1-2 mg/kg/d PO/IV
Interactions
Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Contraindications
Documented hypersensitivity; previous treatment with alkylating agents such as cyclophosphamide, chlorambucil, and melphalan due to prohibitive risk of inducing malignancy; pregnancy is a relative contraindication
Precautions
Pregnancy
D - Unsafe in pregnancy
Precautions
A severe gastrointestinal hypersensitivity reaction may occur during first several weeks of use; symptoms are reversible upon discontinuation of therapy; rechallenge with single dose can cause recurrence of symptoms within a few hours
Methotrexate (Folex, Rheumatrex)
Previously known as amethopterin. Antimetabolite that inhibits dihydrofolic acid reductase. Also used in certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis.
Dosing
Adult
Not established; suggested dose is 7.5 mg PO qwk or 2.5 mg PO q12h for 3 doses/wk; not to exceed 20 mg/wk
Use relatively low doses in elderly people; closely monitor for early signs of toxicity
Pediatric
Not established
Interactions
Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; severe gastrointestinal toxicity and bone marrow suppression has occurred in some patients who have concurrently taken high-dose MTX with some NSAIDs; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines
Contraindications
Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); pregnancy
Precautions
Pregnancy
X - Contraindicated in pregnancy
Precautions
Monitor CBCs monthly and liver and renal function q1-3mo during therapy; monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration; MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)
Follow-up
Prognosis
- Approximately 20% of patients may have a spontaneous remission without specific therapy.
- More than half of patients treated for LC experienced resolution of symptoms after 6 months of treatment, while only 15% of patients had significant persistent symptoms.
- In some patients, the diarrhea may wax and wane over many years; however, more than 80% of patients can expect diarrhea and histologic abnormalities to resolve within 3 years.
- Rare cases with severe and protracted diarrhea have been fatal; these cases are likely thought to be due to epithelial membrane sloughing and resultant altered mucosal permeability.
- Although some small studies have suggested otherwise, microscopic colitis (either CC or LC) does not appear to increase the risk of colon cancer.
Patient Education
- For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine Center and Crohn Disease Center. Also, see eMedicine's patient education articles Colitis,
Celiac Sprue, and Crohn Disease.
Miscellaneous
Medicolegal Pitfalls
- Patients who fail to respond to reasonable medical therapy should be evaluated for other conditions that may mimic LC or CC clinically.
- The adverse effects of corticosteroids and immunosuppressants/immunomodulators may be serious. Such drugs would be difficult to justify in a patient later found to have irritable bowel syndrome or infectious or other causes of colitis or enteritis that should have been treated differently.
- Performing a colonoscopy on patients with chronic diarrhea is commonly accepted and widely practiced, but performing biopsies in all such individuals, even with normal findings on endoscopy, has a low yield. Patients clinically assessed as having diarrhea-predominant irritable bowel syndrome who do not respond to conventional medical therapy may in fact have microscopic colitis, and these patients may benefit from colonoscopy with biopsies.
- Limit biopsies to those subgroups of patients in whom microscopic colitis is most likely.
- Those subgroups would include patients with watery, severe, debilitating, or nocturnal diarrhea; substantial weight loss; an elevated erythrocyte sedimentation rate; or patients who are immunosuppressed.
Special Concerns
- As with the management of inflammatory bowel disease, antidiarrheal and nonimmunosuppressive medications have an acceptable risk in pregnant patients when clinical symptoms are significant and might threaten pregnancy.
- Methotrexate may induce spontaneous abortion and is contraindicated during pregnancy. 6-mercaptopurine and azathioprine may cause fetal harm but so may refractory colitis. Consequently, risk versus benefit must be carefully discussed before prescribing these medications to a pregnant patient.
Multimedia
Media file 1: Lymphocytic colitis (LC) showing marked chronic inflammatory cell infiltrate of the surface epithelium (on right) with preservation of crypt architecture. Subepithelial collagen layer is not thickened.
Media file 2: Collagenous colitis (CC) showing similar inflammatory cell infiltration as in lymphocytic colitis (LC), with the characteristically thickened subepithelial collagen layer.
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Keywords
collagenous colitis, CC, lymphocytic colitis, LC, microscopic colitis
Contributor Information and Disclosures
Author
Eric Goosenberg, MD, Clinical Assistant Professor, Department of Medicine, Drexel University School of Medicine
Eric Goosenberg, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.
Medical Editor
Terence David Lewis, MBBS, FRACP, FRCPC, FACP, Program Director, Internal Medicine Residency, & Assistant Chairman, Associate Professor, Department of Internal Medicine, Division of Gastroenterology, Loma Linda University Medical Center
Terence David Lewis, MBBS, FRACP, FRCPC, FACP is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, California Medical Association, Royal College of Physicians and Surgeons of Canada, and Sigma Xi
Disclosure: Nothing to disclose.
Pharmacy Editor
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment
Managing Editor
Douglas M Heuman, MD, FACP, FACG, AGAF, Chief of Hepatology, Hunter Holmes McGuire Department of Veterans Affairs Medical Center; Professor, Department of Internal Medicine, Division of Gastroenterology, Virginia Commonwealth University School of Medicine
Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association
Disclosure: Nothing to disclose.
CME Editor
Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.
Chief Editor
Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.