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Chronic, watery, non-bloody diarrhea |
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|
|
Normal colonoscopic appearance |
|
|
|
Histopathology: LP inflamm, intraepithelial
lymphocytosis, surface epithelial flattening, |
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+/- thick subepithelial collagen band |
|
Etiology unknown |
|
Pathogen,
antigen, autoimmunity |
|
|
|
|
|
|
|
Mainly case reports; retrospective series |
|
Corticosteroids, 5-ASA, antimicrobials |
|
1 prospective trial |
|
prednisilone 3 - 12 weeks |
|
Decreased fecal frequency 43% |
|
No change in colonic histopathology |
|
Diarrhea recurred rapidly after dc’d |
|
(Sloth et al.
J Int Med 1991) |
|
|
|
|
Anti-diarrheal |
|
Stimulates fluid/electrolyte absorption, |
|
decreases secretion |
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Binds bacterial toxins and bile salts |
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|
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Anti-bacterial |
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Bactericidal and inhibits metabolism |
|
|
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Anti-inflammatory |
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|
|
|
|
|
|
|
9 of 15 refractory patients improved
with bismuth subsalicylate enemas |
|
(Ryder, et al.
Aliment Pharmacol Ther 1990) |
|
|
|
12 of 31 patients improved with
bismuth citrate enemas (=
5-ASA) |
|
(Pullan, et al.
Gut 1993) |
|
|
|
|
|
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|
|
|
Because of its antidiarrheal, antibacterial, and anti-inflammatory
properties, bismuth subsalicylate will resolve both the diarrhea and the
histopathology of microscopic colitis. |
|
|
|
|
Nine consecutively diagnosed patients with
microscopic colitis |
|
4 - Thick subepithelial collagen band |
|
|
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5 - Normal subepithelial collagen band |
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|
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All female, 37-71 years old |
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|
|
Duration of diarrhea 4 mos - 21 yrs |
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|
|
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Eight 262 mg chewable tablets per
day for eight weeks |
|
|
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Pilot study - open label, no placebo |
|
Feasibility and safety of 8 weeks of Rx |
|
|
|
Determine open label response rates |
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|
|
Help plan placebo-controlled trial |
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|
|
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CBC, chem, ANA, bismuth, salicylate |
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|
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Fecal consistency and weight |
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48-Hour stool collection |
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|
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Fecal frequency recorded daily |
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|
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Histology of 24 Bx’s from left colon |
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Flexible sigmoidoscopy |
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|
|
|
Lamina propria cellularity - magnitude, type |
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|
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Thickness of subepithelial collagen layer |
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|
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Number of intraepithelial lymphocytes |
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|
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Integrity of surface epithelium |
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|
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Crypt architecture |
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|
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Clinical |
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< 2
formed or semi-formed BM per day |
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Histological |
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>
50% decrease in histopathology score |
|
|
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|
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Treated 12 patients for 8wks with open-label
Pepto-Bismol (8 chewable tabs/day) |
|
Resolution of diarrhea in 11 patients |
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Resolution of colitis in 9 patients |
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No toxicity or side-effects (constipation in 2) |
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Patients without celiac sprue-no recurrence |
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Patients with celiac sprue - some required
retreatment at 3-6 month intervals |
|
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|
|
|
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No side effects (constipation in 2) |
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|
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CBC, chemistries, liver enzymes - Nl |
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Bismuth levels
5-34 µg/L (safe <100) |
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Salicylate levels - undetectable |
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Well, no further treatment 7of 9 (78%) |
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Well, required retreatment 1of 9 (11%) |
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Continued diarrhea 1of 9 (11%) |
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|
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Treated celiac sprue |
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1
responded ANA negative |
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1
no response ANA 1:640 |
|
|
|
Untreated, newly dx’d celiac sprue
1 responded
ANA negative |
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Bismuth
subsalicylate can improve both the diarrhea and the histopathology of
microscopic colitis, and will be superior to placebo in a randomized,
double-blind, placebo-controlled trial. |
|
|
|
|
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Treatment - 3 tablets three times a day x 8
weeks |
|
Bismuth subsalicylate 262 mg chewable tablets |
|
Identically colored and flavored sucrose-placebo
tablets |
|
Measured parameters |
|
Fecal consistency and weight - 48-Hour stool
collection |
|
Fecal frequency recorded daily |
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Histology of 16 Bx’s from left colon - flex sig |
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Placebo crossed over to active drug |
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|
|
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20 patients with microscopic colitis |
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13- Thick subepithelial collagen band |
|
|
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7 - Normal subepithelial collagen band |
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|
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16 female, 4 male; age 35-78 years old |
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|
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Duration of diarrhea 4 mos - 18 yrs |
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|
|
|
Lamina propria cellularity - magnitude, type |
|
|
|
Thickness of subepithelial collagen layer |
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|
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Number of intraepithelial lymphocytes |
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|
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Integrity of surface epithelium |
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|
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Crypt architecture |
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|
|
|
|
|
|
|
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Well, no further treatment 16 of 22 (73%) |
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Well, required retreatment 5 of 22 (23%) |
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Continued diarrhea 1 of 22 (4%) |
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Well, no further treatment 25 (62%) |
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Well, required retreatment 5 (13%) |
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Well, required adjuvant treatment 8
(20%) |
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Continued diarrhea 2 (5%) |
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|
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* 10 - 50 months |
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|
|
|
Following 8-weeks of treatment : |
|
93% of patients with microscopic colitis
resolve diarrhea |
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74% resolve or have less histologic colitis |
|
No side effects |
|
60-70% require no further treatment |
|
|
|
|
|
|
|
Bismuth subsalicylate is an effective treatment
of microscopic colitis |
|
|
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Retreatment is sometimes necessary but usually
successful |
|
|
|
Apparent predictors of relapse or no response: |
|
Gluten sensitivity, signs of autoimmunity, NSAID
use |
|
|
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|
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Bismuth Calcium |
|
Antibacterial Binding of bile acids |
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Binding of enterotoxins Binding of fatty acids |
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Binding of bile acids Antidiarrheal |
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Antiinflammatory |
|
Salicylate Mannitol |
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Antiinflammatory Alters colonic flora |
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Proabsorptive |
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NSAID use |
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|
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Signs of significant autoimmunity |
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Signs of gluten sensitivity |
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|
Microscopic colitis is present in 5% of treated celiac sprue patients
and is the most common cause of diarrhea following treatment with a GFD |
|
Present in 67% of patients with refractory sprue |
|
Colitis in celiac and refractory sprue
histologically identical to that in patients without sprue |
|
|
|
|
|
|
|
Molecules involved in antigen presentation
to T cells - cell mediated
immune processes |
|
Typed by serologic method - antigenic structure
molecular method - DNA sequence |
|
Certain alleles are tightly associated with and
involved in pathogenesis of celiac sprue |
|
HLA-DQ2
in 90% |
|
HLA-DQ8
in most without DQ2 |
|
|
|
|
|
Tightly associated with class II alleles |
|
HLA-DQ2
90% |
|
HLA-DQ8
most of those without DQ2 |
|
|
|
HLA-DQ alleles present in patients with MC or
refractory sprue not reported previously |
|
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|
Because of the histopathologic similarities and epidemiologic
overlap of microscopic colitis with celiac and refractory sprue, we
hypothesized that the HLA-DQ genes of patients with these sprue syndromes
and patients with microscopic colitis may be similar, and if so, may shed
light on the pathogenesis of the microscopic colitis syndrome. |
|
|
|
|
|
|
HLA-DQ
genotype assessed by serologic
and molecular methods in: |
|
patients with celiac sprue |
|
patients with refractory sprue and MC |
|
patients with the MC syndrome |
|
(with and without subepithelial collagen
thickening) |
|
normal controls |
|
|
|
|
|
|
|
Serum antigliadin IgG and IgA antibody, and antiendomysial IgA antibody
measured |
|
37 patients with the microscopic colitis
syndrome underwent endoscopic biopsy of mid - distal duodenum |
|
Biopsy slides analyzed blindly |
|
|
|
|
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|
Group Positivty rate |
|
Untreated celiac sprue (n=20) 100% |
|
Microscopic colitis (n=63) 75% |
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Normals (n=37) 32% |
|
Treated celiacs (n=11) 9% |
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|
|
|
|
|
|
|
HLA-DQ2,x or DQ1,3 genotype was seen in 96% of celiac sprue, 100% of refractory
sprue with MC, and 91% of patients
with MC syndrome |
|
Serologic tests for celiac sprue are low titer
or negative, but fecal antigliadin antibody tests can show that MC patients
are gluten sensitive |
|
Mild inflammation of small intestine present in
67% of MC; half have mild to moderate villous atrophy |
|
|
|
|
|
1. A
shared set of predisposing HLA genotypes accounts for the epidemiologic
overlap of celiac sprue, refractory sprue, and microscopic colitis. |
|
This suggests that microscopic colitis like
celiac
sprue results from an HLA-directed, T cell-mediated reaction to a luminal antigen. |
|
The ability of celiac patients on a gluten-free
diet to develop colitis implies
that an antigen other than gliadin is etiologic. |
|
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|
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|
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|
|
2. Patients with microscopic colitis may
have mild yet potentially
clinically important gluten sensitivity. |
|
Likely due to the presence of an HLA class II
genotype capable of mounting an immune
response to gliadin. |
|
Speculate gliadin sensitivity is triggered by
the colitis, rather than the converse. |
|
May cause persistence of symptoms despite
successful treatment of the colitis. |
|
|
|
|
|
|
3. In patients with microscopic colitis
genetically capable of gluten-sensitivity, low titers of antigliadin
antibodies and mild small intestinal histopathology occur secondarily to
the colonic inflammatory response, rather than the converse |
|
Serologic tests for celiac sprue are low titer
or negative, but fecal antigliadin antibody tests can show that MC patients
are gluten sensitive |
|
|
|
|
|
Mild gluten sensitivity in microscopic colitis
occurs secondarily to colonic inflammatory response rather than the
converse |
|
“Secondary” gluten sensitivity with MC |
|
Serum antigliadin/antiendomysial Ab: found less often and lower titers than
celiac sprue |
|
Small intestinal inflammation or villous
abnormalities usually mild or absent |
|
Steatorrhea minimal or absent |
|
|
|
|
|
|
|
|
|
Serum antigliadin Ab: less prevalent and lower
titers than celiac sprue;usually IgG or IgA |
|
Serum Antiendomysial Ab: less prevalent than CS |
|
Fecal antigliadin or antitissue transglutaminase
antibody tests are positive |
|
Enteropathy usually mild |
|
L.P. inflammation +/- pva or sva |
|
Minimal or no steatorrhea |
|
|
|
|
|
|
|
HLA-directed T-cell reaction to an antigenic
stimulus in the colonic lumen |
|
Not gluten or other dietary derivative |
|
Related to bacteria or another microorganism |
|
Potentiated by NSAID’s and possibly estrogen
supplements |
|
Antibiotics or other factors related to
alteration of colonic flora |
|
|
|
|
|
Stool fat - assess for steatorrhea |
|
Serum AGA IgG; fecal AGA IgA, ATTA IgA |
|
Stop NSAID’s (including aspirin) |
|
Bismuth subsalicylate tablets 3 tid for 8 weeks |
|
Relapse - small bowel biopsy, re-treat,
gluten-free diet |
|
No response - small bowel biopsy, gluten-free
diet, |
|
increase dose of BSS, add or replace
with cholestyramine,
new protocol to alter colonic flora |
|
|
|
|
|
|
|
Intestinal inflammation in murine models of IBD
requires an enteric flora for development and is inhibited or attenuated by
antibiotics, germ-free conditions, or inoculation with Lactobacillus spp |
|
Fecal diversion in animals and humans attenuates
or prevents inflammation |
|
Primary anatomic areas of intestine in human IBD
are those harboring greatest #’s of bacteria |
|
|
|
|
|
Reduce or prevent exposure to foodstuffs |
|
Bowel rest +/- liquid diets |
|
Suppress bacterial growth |
|
Antibiotics (anaerobic or broad spectrum) |
|
Intestinal lavage |
|
Alter intestinal flora |
|
Lactobacillus supplements (Probiotic) |
|
Poorly absorbed CHO supplements (Prebiotic) |
|
|
|
|
|
Intestinal lavage with PEG/electrolyte solution |
|
Supplementation with Lactobacillus caseii subspecies
rhamnosus (Lactobacillus GG) |
|
More adherent to colonic cells than other
species, aiding colonization
(Goldin et al, DDS
1992) |
|
Low dose lactulose (10-20 gram/day) |
|
Lowers colonic pH promoting growth of Lactobacilli
(Florent
et al, JCI 1985) |
|
|
|
|
|
|
|
Seven are improved |
|
One did not complete protocol |
|
Further details are forthcoming |
|