Microscopic colitisChris J. J. Mulder1, Ivar M. Harkema2, Jos W. R. Meijer3
1 Department of Gastroenterology, Vrije Universiteit Medisch Centrum / Free University Medical Centre, Amsterdam, the Netherlands
2 Department of Gastroenterology, Ziekenhuis Rijnstate / Rijnstate Hospital, Arnhem, the Netherlands
3 Department of Pathology, Ziekenhuis Rijnstate / Rijnstate Hospital, Arnhem, the Netherlands
Mulder CJJ, Harkema IM, Meijer JWR. Microscopic colitis. Folia Gastroenterol Hepatol 2004; 2 (2): 81 - 86.
Abstract. Microscopic colitis is viewed as an umbrella term applicable to both lymphocytic and collagenous
colitis. The first case was published in 1976, a new entity with chronic watery diarrhoea with lymphocytic colitis,
with or without a subepithelial collagen deposition. Patients are usually middle-aged women. The pathogenesis
is unknown. The response to steroids and the female predominance underscores an autoimmune disease. Up to
40 % non-steroidal anti-inflammatory drugs-induced and lansoprazole-induced microscopic colitides are well-
known. Biopsies during sigmoideoscopy in unexplained diarrhoea must be standard. Treatment is empirical.
The most important step is to ban all non-steroidal anti-inflammatory drugs and other microscopic colitis indu-
cing agents. Immunosuppressive treatment must be considered. However, the disease has a benign course and
Key words: microscopic colitis, lymphocytic colitis, collagenous colitis
Microscopic colitis (MC) is viewed as an umbrella
with a female/male ratio from 3 - 20 : 1 (27,44). Most
term applicable to both lymphocytic colitis (LC) and
are in the fifth or sixth decade, age range of 10 - 90
collagenous colitis (CC) (28,29,38). The first case of
years with a mean age of 50 - 60 years (6,36,44). The
CC was published in 1976 by Lindström, who descri-
incidence of CC is estimated between 0.2 - 2.3 / 105
bed a new entity in which chronic watery diarrhoea
inhabitants (27). In LC there is a less pronounced pre-
was associated with a thick, subepithelial collagen
dominance of women 1.6 - 3 : 1 (36). The peak onset
deposition in biopsy samples of endoscopically nor-
for LC is similarly in the fifth or sixth decade, the same
mal colonic mucosa (29). The term lymphocytic colitis
age range as CC, with a mean of 50 - 65 years
was proposed in 1989 considering the absence of the
(36,44). Differences in incidence probably reflect the
collagen band on histological evaluation (28). These
lack of unification of these entities. Familial clustering
entities are now generally recognized and MC has
of CC has been recognized (25,42,44).
become a common condition of unknown cause
especially affecting the large bowel (27). MC features
are chronic watery diarrhoea without blood, abdomi-
The pathogenesis of MC is unknown. There are
nal pain, normal blood test results, no signs of malab-
many features, which suggest that MC might be an
sorption, normal microbiology, radiology and endo-
autoimmune disease. The response to steroids and the
scopic findings. Histopathology reveals a thickening of
female predominance emphasise this hypothesis.
the subepithelial collagen layer beneath the basement
Remission has been reported during pregnancy (6).
membrane throughout the colon with lymphocytic
A luminal agent or an immunological reaction against
infiltrates in the lamina propria. The pathogenesis and
significance of these findings are still unknown.
Table 1 Reported associations of microscopic colitis and other
Therapeutical options are mainly based on case
reports. However, in recent literature budesonide and
Association in %
azathioprine seem promising. In some cases, the
Patients with CC are usually middle-aged women,
an endogenous antigen produced by enterocytes
might trigger the disease (6). Immunoglobulin IgM is
Adverse drug effects are implicated to cause mic-
increased in CC (40 %) (9). Positive antinuclear antibo-
roscopic colitis. Best known are non-steroidal anti-
dies were found in 30 % - 50 % (36,44). P-ANCA was
inflammatory drugs (NSAIDs)-induced and lansopra-
found positive in 10 - 14 % of patients (44). Up to 40 %
zole-induced MC (16,27,49). NSAIDs-induced MC is
of patients have one or more associated autoimmune
characterized by histopathological features of CC and
diseases (36). Coeliac disease in 6 - 40 % (36,39), thy-
hypoproteinaemia. This might be caused by NSAIDs-
roid diseases in up to 20 % (20,36), diabetes mellitus
induced protein-losing enteropathy. The watery stool
in 10 % and rheumatoid arthritis in 2.5 % of MC pati-
can even obtain mucus and/or blood. Ulcerations and
ents are reported. Other autoimmune diseases have
perforations have been described (49). NSAIDs might
been reported such as CREST syndrome, Sjögren’s
be an aetiologic factor in CC. NSAIDs inhibit the synt-
syndrome, psoriasis, Raynaud phenomenon, dermato-
hesis of prostaglandins, especially of PGE2, and give
myositis, polymyalgia rheumatica, Wegener’s granulo-
rise to an increased production of collagen (16). Some
matosis, Beh,cet’s disease and systemic lupus erythe-
suggest that colitis caused by NSAIDs should be clas-
matodes (36). Intraepithelial lymphocytes in patients
sified as a different entity, because of differences in
with CC are increased. These lymphocytes are predo-
clinical features (49). Withdrawal of NSAIDs is usually
minantly CD8+ T-lymphocytes with the α/β heterodi-
followed by improvement of the clinical and histologi-
mer, whereas the lymphocytes in the lamina propria
cal abnormalities. These patients seem to be more
are dominated by CD4+ T-lymphocytes. However, the
prone to use aspirin or other NSAIDs (30 - 60 %) (36).
distribution of CD8+ T-lymphocytes in the epithelium
However, withdrawal did not mean a disappearance of
versus CD4+ T-lymphocytes in the lamina propria is
the same as in normal intestinal mucosa.
Lansoprazole-induced MC shows histopathological
abnormalities as seen in CC and LC. The mechanism
is unexplained. Toxic or immunological factors may
The observation that diversion of the faecal stream
be involved. Symptoms are watery stool and mild
can normalize or reduce the histopathological chan-
abdominal pain. These complaints can occur in up to
ges in CC support the hypothesis of a luminal agent
5 % of lansoprazole-users (23). Discontinuing the
as a possible aetiological factor (24). These presumed
drug resolves the complaints and histology normali-
agents in the faecal stream presumably cause epithe-
zes (43). Similar observations about other PPI have
lial leakage and vacuolisation of the enterocytes.
been reported as case-reports, but not confirmed by
They become flattened or cuboidal without a cove-
others (43,48). Other agents causing MC are ticlopidi-
ring mucin layer. This weakens the epithelial barrier
ne (LC) (5), cimetidine (22), ranitidine (LC and CC) (3),
resulting in thickening of the subepithelial collagen
cyclo 3 fort (LC) (4,44), carbamazepine (LC) (31), sim-
layer, constructing a new barrier. The predominant
vastatin (17), vinca alkaloid (LC) (19), tardyferon (LC)
abnormalities of MC in the proximal colon support the
luminal agent hypothesis. The luminal agent might be
phagocytosed by macrophages and then presented
to immunocompetent cells stimulating the immune
A synthesis dysfunction in the fibroblast sheet has
system and initiate a cascade of inflammatory reacti-
been reported. Decreased levels of interstitial collage-
ons involving fibroblast proliferation possibly respon-
nase (Matrix Metalloproteinases MMP-1) and increa-
sible for the excessive collagen deposits. Microbiolo-
sed expression of TIMP-1, a tissue inhibitor of MMP-
gic studies in MC give no clear explanation. Yersinia
1, have been found in patients with MC suggesting
enterocolitica has been suggested as a factor in
that reduced matrix degradation and not overactivati-
developing MC (7). Resolution of CC after antibiotic
on of matrix synthesis leads to subepithelial accumu-
treatment for Helicobacter pylori supports the micro-
lation of matrix proteins like collagen type III and espe-
biological hypothesis (34). Nitric oxide and plasma
cially type IV and tenascin. These findings indicate
nitrate and nitrite levels are increased in CC patients.
that inadequate local fibrinolysis is a major cause of
It is not clear whether nitric oxide is produced by the
collagen accumulation in CC (33,45). Smoking has
inflamed mucosa or is of bacterial origin (30,44).
been suggested to protect against MC (36,44).
junctions (15). The definitive diagnosis of MC relies on
The onset of MC is in 60 % insidious, and in 40 %
histologic diagnosis on biopsies taken from the colon,
(sub)acute. The symptoms are watery diarrhoea (4 -
10 stools per day), nocturnal diarrhoea, faecal urgen-
1) A diffuse thickening of the collagen layer beneath
cy, bloating, abdominal pain, and meteriorism. Some-
times symptoms are intermittent. Weight loss is quite
throughout the colon in CC but absent in LC with
common. Dehydration is uncommon. When sticky
lymphocytic infiltration in the lamina propria in CC
faeces is found one should suspect coeliac disease.
and more pronounced in LC. The presence of more
Vice versa persistent diarrhoea in treated coeliacs
than 10 intraepithelial lymphocytes per 100 epithe-
means strong suspicion of MC. The course of MC is
lial cells seems specific and helpful for diagnosing
relapsing and benign (36). Sometimes, patients beco-
CC and/or LC (36). The thickness of the subepithe-
me socially disabled caused by frequent diarrhoea.
lial layer in normal individuals varies from 0 - 3
Although the majority of patients are female, the
µm (29). A thickness of 10 µm or more has been
symptoms and progression is similar in men and
accepted to establish the diagnosis CC. A collagen
women. Laboratory findings can show a mild eleva-
thickness exceeding 45 µm might be an epithelial
ted erythrocyte sedimentation rate, a normocytaemic
barrier (20,34). Stool weight correlates with severi-
anaemia and occasionally abnormalities in serum
ty of mucosal inflammation and not with collagen
levels of IgG, C3 or C4 complement (8). Differences in
thickness (44). The basement membrane consists
HLA haplotype between CC and LC have been sug-
of collagen type IV. The collagen layer in CC bene-
gested. In LC there is an increase in HLA A1 and
ath the basement membrane consists of collagen
a decrease in HLA A3 haplotype whereas in CC there
types I, III and IV, and VI. Collagen I and III are
are no differences between patients and controls (6).
thought to be important in tissue repair (6,16).
However, data are limited. Microbiology remains
However type VI collagen might be considered to
negative. Steatorrhoea and increased excretion of fae-
be a pathologic collagen deposition (16).
cal leukocytes are reported in more than 50 % of pati-
2) The inflammation in the lamina propria is domina-
ents (44). P-ANCA and other autoimmunologic factors
ted by lymphocytes and plasma cells. Eosinophils
are found positive, implicating a link with auto-immu-
and mast cells can be found but neutrophils are
ne diseases. Colonoscopy is the preferred diagnostic
very rarely observed (6). Cryptitis and crypt abces-
tool given the possibility for proximal and distal biop-
ses do not exclude the diagnosis of MC (26).
sies. Radiology is not helpful in recognizing MC.
3) The epithelial cells appear to be flattened and
vacuolized. Intraepithelial lymphocyte infiltration is
DIAGNOSIS AND HISTOPATHOLOGY
present but is more prominent in LC. A histopatho-
Diagnosis is based on classical symptoms of chro-
logic diagnosis can be made with endoscopy. Sub-
nic watery diarrhoea without blood, abdominal pain,
tle endoscopic changes in up to 30 % of cases,
normal blood test results, no signs of small bowel
such as mucosal oedema, erythema or mucosal
malabsorption, and normal microbiology, radiology
paleness have been described. Detachment of the
and endoscopy. The pathophysiology of the watery
surface epithelium can occur. Haemorrhagic
diarrhoea has been investigated, with special interest
mucosal laceration after insufflation in CC patients
for the disturbed electrolyte and water transport in
with a thick collagen layer has been recognized
CC (15). The mechanisms for diarrhoea in MC inclu-
(21). Taking biopsies of macroscopical normal
de: I) malabsorption of fluid due to hampered trans-
mucosa in cases of diarrhoea is mandatory (27).
port and to collagenous bands. II) secretory diarrho-
Considering the patchy distribution of MC in the
ea due to anion (chloride) secretion, and III) "leak flux-
colon, sigmoideoscopy seems insufficient. Rectal
induced diarrhoea" due to an impaired epithelial bar-
biopsies might be insufficient in up to 75 % becau-
rier secondary to lymphocyte infiltration and thicke-
se the collagenous layer seems more prominent in
ning of the collagenous band which is comparable
the proximal colon. Others could not reproduce
with data in Yersinia colitis (15), and to a passive back
any diagnostic accuracy between sigmoideoscopy
leak of ions and water into the intestine lumen. This is
and colonoscopy (32,40,44). Subepithelial collagen
probably related to decreased function of the tight
deposits are reported in case reports in duodenum
and ileum mucosa in CC-patients, so-called colla-
matory bowel disease is not significant different from
genous enterocolitis or as a primary entity (6). Col-
prednisolone but it leads to significant fewer side
lagenous gastritis in combination with CC has
effects (45). It has effects on both the inflammatory
been reported (16,47). Collagenous and lymphocy-
mucosal changes as well as the thickness of the col-
tic gastritis seems strongly associated with coeliac
lagen band (12,33). It is recommended to treat these
disease in up to 40 % of the patients (41). Consi-
patients during a course with 9 mg budesonide
dering the benign course of the disease without
(2,10,33). Azathioprine and methotrexate should be
any evidence of premalignant potential there
considered in steroid-dependent and steroid-refrac-
seems to be no need for routine follow-up colo-
tory patients (35,46) or as steroid-sparing agent. Data
concerning these therapeutics are limited. Azathiopri-
ne seems successful in a dose of 2 mg/kg daily (46).
The long term follow-up results are promising with
Treatment of MC is still empirical. The first and most
high response rates (13). In a minority of patients the
important step is to ban all NSAIDs and other colitis
diarrhoea remains severe despite treatment. In these
inducing medications (44). Additional medication is
patients, diverting ileostomy with or without colecto-
mostly symptomatic such as bismuth subsalicylate,
my is effective, interestingly showing normal ileosto-
antidiarrhoeals (loperamide, dephenoxylate, atropine)
mic volumes postsurgery (44). These data are similar
and high fiber diet. Although bismuth is effective and
for CC and LC. Abdo et al. (1) investigated several cli-
well tolerated its use in Western Europe is limited
nical and histological predictors of response in the
because it is not regularly available (2). Step two:
treatment of CC. They found that the age of onset
5-ASA agents might be helpful (45% response)
determining. Older patients were most likely to be
(13,27). Bonner et al. found a short term response in
controlled with antidiarrhoeal agents or no medicati-
17/22 (81%) patients using an average 5-ASA dose of
on. The younger patients needed more medication.
1500 mg during a-six week period (13). Step three:
NSAIDs use at time of presentation was associated
(topical) corticosteroids, immunosuppressives such as
with greater need for 5-ASA and steroid therapy
azathioprine, and octreotide and step four, as a last
(1,27). Interestingly, cessation of NSAID in 60 % did
resort, surgery. In our experience step four has never
not affect the course. Also the degree of inflammati-
been necessary. In some studies 40 % of the subjects
on of the lamina propria can be used as a predictor.
had complete resolution of symptoms without therapy
The more intense the inflammation, the more patients
(36). The first group of medication is often well tolera-
are likely to fail on symptomatic treatment (1).
ted showing good beneficial effects (36).
If the patient presents with severe watery diarrhoea,
step two medication is introduced. If there is no res-
MC forms a subclass of inflammatory bowel disea-
ponse, corticosteroids are the next step. The respon-
se. Some suggest a gradual transition from a LC-like
se is 80 % - 100 % but relapses occur during tape-
colitis to CC. Wilcox et al. (48) described a patient with
ring. Steroids have many side effects. For most, the
histological findings of CC and later LC in reaction to
usually benign course of MC does not justify prolon-
lansoprazole. The thickening of the subepithelial colla-
ged use of steroids. Budesonide is a topical acting
gen band in CC is believed to be secondary to chro-
steroid with a high lipophilicity leading to both a high
nic inflammation. Also the similarity in treatment sug-
receptor-binding affinity and a high first-pass effect in
gests a common pathologic pathway. The collagen
the liver. Clinical efficiency of budesonide in inflam-
band is the latest microscopic factor to resolve during
treatment, stressing the more chronic component. The
Table 2 Reported treatment options for microscopic colitis
diagnosis is often only assessed by biopsy. It is
Response (%) Reference
recommendable to obtain at least two specimens
from transverse colon, descending colon, sigmoid
colon, and rectum. This should lead to the diagnosis
in the majority of the patients. Colonoscopy should be
used in patients with high suspicion for CC or LC. This
is because of the declining histopathological changes
from the proximal to the distal colon. The aetiology of
similar. First of all, NSAIDs and other colitis-inducing
MC is unknown. Three major theories are suggested.
medication should be withdrawn. In mild diarrhoea,
First, the lymphocytic infiltration is probably based on
fibers and antidiarrhoeal agents can be successfully
an adequate immunoresponse to a foreign luminal
used. In some cases antibiotics such as erythromycin
agent (toxin, microbiological or other substrates).
and metronidazole seemed effective. If this is not suf-
Secondly, the CD4 and CD8 lymphocyte distribution
ficient, 5-ASA can be added. For more severe mani-
in this form of colitis show similarities with coeliac
festations of diarrhoea (stool frequency > 5 times/day)
disease. The latter suggesting a possible autoimmune
topical steroids such as budesonide are the drug of
aetiologic factor. Associations with other autoimmune
choice. The symptoms resolve quickly and overall it is
diseases such as thyroiditis, rheumatoid arthritis, ANA
well tolerated. If the disease is relapsing or it is refrac-
positive diseases, diabetes mellitus and coeliac dis-
tory, long-term immunosuppressives should be consi-
ease support this theory. Thirdly, the collagen band
dered. The first results with azathioprine are promi-
seems secondary to disorders in collagen matrix and
sing. Usually the disease has a benign course and
in fibrinolytic factors. The treatment in CC and LC is
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Address for correspondence:
epiphenomenon of autoimmune disorders? Rom J Gastroente-
Professor Chris J.J. Mulder, VU Medical Centre, Department
of Gastroenterology, P. O. Box 7057, 1007 MB Amsterdam,
40.Shah DI, Fenoglio-Preiser C, Bleau BL, Giannella RA. Useful-
ness of colonoscopy with biopsy in the evaluation of patients
David Borde Resume addendum: Background: I started my photography career with Peter Elliott Productions, Inc. in May of 1983. For 2 years I assisted this top Chicago photographer and film director in the field of large format food and product photography. During this time I also broke into the film industry where I developed my skills as a prop-master and rigger for special effects in film. In 198
SIMULTANEOUS DETERMINATION OF PHENACETIN AND CAFFEINE USING A DOUBLE BEAM SPECTROMETER To simultaneously determine the concentrations of phenacetin andcaffeine in an unknown aqueous solution using scanning UV-visible spectrophotometryat two wavelengths. Introduction: This experiment is a portion of the standard analysis for the three activecomponents in (Aspirin/Phenacetin/Caffeine) tablet