1. health and fitness
2. disease

Microscopic Colitis:
diagnosis, epidemiology
and management
Paul L Beck MD PHD University of Calgary,
Division of Gastroenterology, Foothills Hospital
Nilesh Chande MD University of Western Ontario,
Division of Gastroenterology, London Health Sciences Centre
Disclosures
• Dr. Beck has no disclosures
• Dr. Chande:
– Speaker’s honoraria – Abbott, Schering
– Advisory board – Ferring, Abbott, Axcan
– Travel support - Schering
CDDW/CASL Meeting Session: (Faculty Template Slide)________
CanMEDS Roles Covered in this Session:
9
Medical Expert (as Medical Experts, physicians integrate all of the CanMEDS Roles,
applying medical knowledge, clinical skills, and professional attitudes in their provision of
patient-centered care. Medical Expert is the central physician Role in the CanMEDS
framework.)
9
Communicator (as Communicators, physicians effectively facilitate the doctor-patient
relationship and the dynamic exchanges that occur before, during, and after the medical
encounter.)
Collaborator (as Collaborators, physicians effectively work within a healthcare team to
achieve optimal patient care.)
Manager (as Managers, physicians are integral participants in healthcare organizations,
organizing sustainable practices, making decisions about allocating resources, and
contributing to the effectiveness of the healthcare system.)
9
Health Advocate (as Health Advocates, physicians responsibly use their expertise and
influence to advance the health and well-being of individual patients, communities, and
populations.)
9
Scholar (as Scholars, physicians demonstrate a lifelong commitment to reflective learning,
as well as the creation, dissemination, application and translation of medical knowledge.)
Professional (as Professionals, physicians are committed to the health and well-being of
individuals and society through ethical practice, profession-led regulation, and high personal
standards of behaviour.)
Objectives
Understand microscopic colitis with respect to:
1. Histological features
2. Epidemiology and risk factors
3. Pathogenesis
4. Management
72 yo woman with non-bloody
diarrhea x 8 months
• HPI;
– 6 liquid BMs per day,
– Normal colonoscopy 3 months
ago (no Bx done)
– No; fevers, weight loss or
extraintestinal features of IBD
• PMHx;
– Reflux; Rx; lansoprazole X 1 year.
– Hypothyroidism on Synthroid,
normal TSH.
– Osteoarthritis-Rx; diclofenac and
ibuprofen
– smokes 1 ppd x 53 y.
72 yo woman with non-bloody
diarrhea x 8 months
• Investigations to date;
– Normal;
• CBC, lytes, alb, ESR,
CRP
• TTG, IgA
• Stool C+S, O+P, C diff
toxin assay
• Colonoscopy; normal
Question
• How many of you use terms
– Microscopic Colitis
– Collagenous Colitis
– Lymphocytic Colitis
• Is differentiating these diagnoses of
clinical significance?
The History of Microscopic Colitis
• 1976 – Freeman and Lindstrom
independently reported the features of
collagenous colitis (CC)
• 1980 – Read applied the term
“microscopic colitis” to a group of patients
with chronic diarrhea and endoscopically
normal appearing mucosa
• 1989 - Lazenby et al first described
lymphocytic colitis (LC)
Ann R Coll Physicians Surg Can 1976;9(45), Pathol Eur 1976;11:87-9, Gastroenterology 1980;78:264-71,
Hum Pathol 1989;20:18-28.
Collagenous Colitis
Histological Criteria
1) thickening of a subepithelial
collagen layer of more than
10 μm*
2) inflammation** in the lamina
propria consisting of mainly
lymphocytes and plasma cells;
and
3) epithelial damage, such as
flattening and detachment.
*Some studies suggest a cut-off
limit of 15 μm to 30 μm
**increased IELs may be present
but is not necessary for the
diagnosis
Lymphocytic Colitis
Histological Criteria
1) intraepithelial lymphocytosis
(≥ 20 IEL per 100 surface
epithelial cells)
2) inflammation in the lamina
propria consisting of mainly
lymphocytes and plasma
cells
3) epithelial damage, such as
flattening and detachment
4) subepithelial collagen layer
not present or if present it
must be less than 10 μm.
Incidence of Microscopic Colitis
• Olesen et al Orebro, Sweden. Gut
2004;53:346–350
• incidence of MC has increased from
1993-5 to 1996-8;
collagenous colitis 3.7/105 Ö 6.5/105
lymphocytic colitis 2.4/105 Ö 5.1/105
• 10% of all patients with non-bloody
diarrhea had MC
• 20% of those >70 years had MC!
• Incidences of CC and LC=Crohn’s
disease in Sweden
• Incidence of MC is close to ulcerative
colitis.
Incidence of Microscopic Colitis
Point Prevalence MC; 10 - 103 per 100,000
CLINICAL GASTROENTEROLOGY AND
HEPATOLOGY 2008;6:35–40
Canadian Data
Calgary Health Region
CLINICAL GASTROENTEROLOGY AND
HEPATOLOGY 2008;6:35–40
Genetic
Pathophysiology of MC
•Differential HLA expression
(HLA DQ2)
•Family clusters
•Associated with diseases with
strong genetic component
Altered immune
response
•K T cells, mast cells,
plasma cells, fibroblasts,
eosinophils
•Th1 profile;
•K K INFγ, IL-15, TNFα
•KPGE2, TGFβ
Infectious
•Reports of enteric infection preceding MC
•Fecal stream diversion can decrease MC
•Some response to antibiotic therapy
Factors implicated in the
pathogenesis of diarrhea in
MC
•Inflammatory mediators
•Bile salt injury
•Decreased net Na+, Cl–
absorption
•Collagen band may act as a
diffusion barrier
•L tight junctional protein
expression (E-cadherin and ZO-1)
The Terminal Ileum Can Be
Affected in MC.
• Terminal ileal IEL counts (per 100);
–
–
–
–
–
11.8 ± 1.8 in LC
10.3 ± 1.9 in CC
2.8 ± 0.4 in Crohn’s colitis
3.1 ± 0.4 in Ulcerative colitis
2.2 ± 0.2 in normal controls
• The presence of >5 IELs/100 EC in terminal
ileum biopsies was highly specific for LC and CC
(specificity 98%, sensitivity 73% (LC) and 56%
(CC).
Am J Surg Pathol 26(11): 1484–1492, 2002.
Is there is an overlap between MC,
Celiac Disease and IBD?
• The histology of LC and IBD can be similar Anat Pathol 2005;12(4):203
• K IELs in the ileum of both MC and celiac disease Dig Liver Dis
2006;38(11):815-9, Am J Surg Pathol 26(11): 1484–1492, 2002.
• HLA types permissive for celiac are common in MC (HLADQ2) Am J Gastro.2000;95(8):1974-82, CLIN GASTRO. HEP. 2008;6:35–40.
• Progression from MC to UC or CD has been described J Clin
Gastro. 2001;32(5):435-8 63-66, Can. J Gastro.2007;21(5):315-8, Inflam. bowel diseases
2007;13(10):1321.
• 10 fold increase in IBD in celiac patients Scand J Gastroenterol
2007;42(10):1214-20.
• Celiac patients; K 1st degree relatives with IBD Inflam. bowel diseases
2003;9(5):321-3
• 12% of LC patients had a family history of UC, CD or celiac
disease. Gut 2004;53:536–541
• Celiac disease shares two linkage regions with IBD: 5q31
(CELIAC2 and IBD5) and 19p13 (CELIAC4 and IBD6) Curley et al
Eur J Hum Genet 2006;14(11):1215-22 .
Why did she get MC?
Microscopic Colitis
Risk Factors and Disease Associations
• Increasing age
• Female gender
• Autoimmune Disease
– Thyroid Disease
– Celiac Disease
– Diabetes
– Sjogren’s Syndrome
• Past or Current history of Malignancy
• Solid Organ Transplantation
• Smoking
• Medications
Autoimmune Diseases are More
Common in MC
Gut 2004;53:536–541
Likelihood that a drug causes
Microscopic Colitis
High Likelihood
Intermediate Likelihood
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Aspirin
Acarbose
Lansoprazole
Cyclo3 Fort*, Cirkan*
NSAIDs
Ranitidine
Sertraline
Ticlopidine
*extract from Ruscus aculeatus,
hesperidine methylchalcone and
ascorbic acid)
Carbamazepine
Flutamide
Lisinopril
Modopar (levodopa and benserazide).
Oxetorone
Paroxetine
Simvastatin
Tardyferon (iron and ascorbic acid)
Vinburnine
Beaugerie & Pardi Aliment Pharmacol Ther
2005; 22: 277–284.
5
Past or present malignancy in a
group of 164 MC patients
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Number of Patients With Microscopic
Colitis and Cancer
Patients with MC may have an
increased risk of malignancy
Cancer Type/Location
CLINICAL GASTROENTEROLOGY AND
HEPATOLOGY 2008;6:35–40
The Risk of Microscopic Colitis in Solid-Organ
Transplantation Patients is 50x Greater than
the General Population
• In the Calgary Health Region 0.9% of MC were kidney,
kidney/pancreas, and liver transplantation recipients.
• Point prevalence; 8.8/1000 transplantation recipients.
• Annual incidence rate; 5.0 cases/1000 person-years.
• SIR of developing MC after transplantation; 50.5
• Average age of diagnosis of MC: 49 years.
• Average time of onset from txpl; 67 months.
• Average time from onset of diarrhea to diagnosis of
MC; 30 months.
• All patients responded to MC-specific therapy.
Transplantation 2008;85: 48–54
72 yo woman with non-bloody
diarrhea x 8 months
• How to investigate?
– Do you screen all for
celiac, thyroid
problems?
– Since TTG is not very
sensitive in March 1-2
celiac disease… do you
do an upper scope?
– Sig vs full
colonoscopy?
Sigmoidoscopy can miss up to 35%
of MC.
• MC was restricted to the right colon in 3/13
(23%). Thijs et al;
• 27% false-negative rate in a group of patients
with collagenous colitis if only biopsies were
taken within the distal 60 cm (sigmoidoscope).
Tanaka et al;
• Only 66% of rectosigmoid specimens were
diagnostic. Offner et al;
• 97% of cases of chronic diarrhea could be
diagnosed with sigmoidoscopy (122 of 809 had
diagnostic bx, 80/122 were MC). Fine et al
Neth. J Medicine;2005:63;137-40, Gut 1992;33:65-70,
Hum Pathol 19998:30;451-7, Gastrointest Endosc 2000:51;318-26.
The only agents that have
been well studied
Meta-analyses by Chande et al
2008, 2011 Cochrane Database Syst
Rev.;
•Budesonide is effective for the
treatment of CC and LC (clinical
and histological improvement).
•The evidence for benefit with
bismuth subsalicylate,
mesalamine, cholestyramine is
weaker.
•No data to support probiotics
•Budesonide also maintains
remission and improves quality
of life.
Can J Gastroenterol Vol 17 No
7 July 2003
Stop any high or
intermediate risk drugs
associated with MC
Often not effective alone if
severe diarrhea and/or
abdominal pain
Budesonide has the highest
success rate and better
tolerated. (9 mg/d x 8 weeks
vs 9, 6, 3 mg/d taper)
Of 47 patients we have
treated all but one
responded to budesonide,
the other patient responded
to loperimide and
cholestyramine
Rule out other disease
states! Those that relapse
with taper of budesonide
consider Aza/6MP.
Only a few case reports of this. Would only
consider after exhausting all other avenues
of therapy and a few second opinions!
Disease Course of MC
• Lymphocytic colitis: a retrospective
clinical study of 199 Swedish patients
Olesen et al Gut 2004;53:536–541
– chronic intermittent in 30%
– chronic continuous in 7%
– a single attack in 63% (duration was 6 (4–11)
months
• More than 80% of treated patients
improved on corticosteroids
(prednisone or budesonide)
Long term management
• Incidence of continued problems?
– Most respond (>80% in most studies).
• Following budesonide (9mg/d x 6-8 wk) the relapse rate can
be as high as 60%.
– median time to relapse 2 wk
• Relapse is more common in patients <60 y.
• Follow-up?
– Follow symptomatically
• Maintenance therapy?
– Budesonide 6 mg/day effective
• Cancer risk?
– Nil noted to date
Aliment Pharmacol Ther. 2005:22; 1115-9