1. Microscopic colitis and focal active colitis: what’s new?
Professor Neil A Shepherd
Gloucester & Cheltenham, UK

2. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

3. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

4. Microscopic colitis: a history
1976 Lindstrom first described one common type: collagenous colitis
1980 Read recognised the association of normal endoscopy with inflamed biopsy material
1982 Kingham et al first coined the term microscopic colitis
1989 Lazenby et al first described the other common type: lymphocytic colitis
2000s other subtypes described and recognised

5. Microscopic colitis as a concept
normal colonoscopy
chronic watery diarrhoea without blood
significant, usually chronic, inflammation on biopsy
varied histological patterns
does it require colonoscopic normality?
strong association with drugs
diarrhoea is the commonest recorded complication of drug therapy
how many cases are due to microscopic colitis?
used to be considered rare – a disease of private practice!!
now increasingly recognised throughout Europe and the World
I see 50 cases + a year

6. Microscopic colitis - epidemiology
there is now considerable and increasing evidence (especially from Scandinavia) that these diseases (CC & LC) are common
as common, if not commoner, as chronic inflammatory bowel disease in Sweden (each equal to CD with combined rate equal to UC)
CC 4.9 per 10,000; LC 5.7 per 10,000
CC 75-90% female with mean age of 64
LC 60-70% female with mean age of 59
Olesen et al, 2004

7. Microscopic colitis
a concept that remains of considerable importance in colorectal pathology
it is often misdiagnosed by pathologists as ‘mild chronic inflammatory bowel disease’, especially ulcerative colitis
true chronic inflammation infers a loss of the normal chronic inflammatory cell gradient in the lamina propria and basal plasma cells
the caecum shows an increased round cell infiltrate in the lamina propria and an enhanced intra-epithelial lymphocytosis, normally, and this should not be taken as evidence for microscopic colitis

8. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

9. Collagenous colitis there may be endoscopic abnormality
mucosal tears with bleeding
Cruz-Correa et al, 2002
submucosal dissection with gas evident on barium enema
Mitchell et al, 2004
modest pseudo-membrane material
ESPECIALLY in the right/transverse colon

10. Collagenous colitis: this month’s case
there may be endoscopic abnormality
66F
six month history of watery diarrhoea
endoscopy: white line with central crack the complete length of the transverse colon
histology: classical collagenous colitis

11. Colonoscopic abnormalities in microscopic (collagenous) colitis
Koulaouzidis A, Saeed AA. Distinct colonoscopy findings of microscopic colitis: Not so microscopic after all? World J Gastroenterol 2011; 17:

12. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

13. ‘Mixed’ microscopic colitis: this month’s case
61F
two year history of watery diarrhoea
colonoscopy normal
histology: classical collagenous colitis only in right and mid colonic biopsies
with IEL count of 35, especially in surface epithelium

14. Collagenous colitis & lymphocytic colitis
in CC, IEL counts vary from normal to those found in lymphocytic colitis
may coexist with or follow lymphocytic colitis
lymphocytic colitis
collagenous colitis ?

15. Intra-epithelial lymphocytes (surface, median per 100 epithelial cells)
normal 3
ulcerative colitis 4.5
acute colitis 5
lymphocytic colitis 37
Brainerd diarrhoea 18.5
collagenous colitis 22

16. Lymphocytic colitis and collagenous colitis
similar:
age
autoimmune diseases
arthritis
diarrhoea & abdominal pain
NSAIDs and other drugs
dissimilar:
sex ratio (CC more females)
smoking (LC patients more often non-smokers or ex-smokers)
Baert et al, 1999

17. Collagenous colitis and lymphocytic colitis
cases are described of LC becoming CC
most cases stay pure
both associated with certain causes, especially drugs
similar treatments successful (in some patients)
other associations not similar (LC and coeliac disease)

18. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

19. Microscopic colitis – potential confusion with CIBD
minimal change colitis
IBD with little or no colonoscopic abnormality
Lennard-Jones, JE
UC with rectal sparing
Spiliadis et al, 1987
clinical and endoscopic correlation are critical: bloody diarrhoea will not be microscopic colitis

20. Microscopic colitis mimicking CIBD
150 cases of MC, both LC and CC
histological features associated with CIBD not uncommon in CC and LC
presence of these features should not necessarily be interpreted as evidence against either CC or LC
Ayata et al. Prevalence and significance of inflammatory bowel disease-like morphologic features in collagenous and lymphocytic colitis.
Am J Surg Pathol 2002; 26: LC CC
association
CAA & PCM
14%
44%
worse symptoms
acute crypt changes
38%
30%
antibiotic treatment
ulceration 0%
2.5%
endoscopic
changes
CAA = crypt architectural abnormalities
PCM = Paneth cell metaplasia

21. Microscopic colitis and CIBD
BUT microscopic colitis and CIBD can coexist
both are common diseases
microscopic colitis can complicate treatment given for CIBD

22. Microscopic colitis: what’s new?
Definitions & diagnosis
Endoscopic changes
Relationship between lymphocytic and collagenous colitides
Relationship between MC and inflammatory bowel disease
New types of microscopic colitis

23. Microscopic colitis – ‘new types’
microscopic colitis with giant cells
Libbrecht et al, 2002
four cases: 3 with CC, 1 with LC
fusion of subepithelial macrophages (CD 68 +)
note apoptotic activity

24. Microscopic colitis – ‘new types’
microscopic colitis with granulomatous reaction
Saurine et al, 2004
association with NSAIDs, allopurinol & antibiotics
cryptolytic and superficial granulomas
with thanks to Bob Eckstein, Sydney, Australia

25. Microscopic colitis – ‘new types’
pseudomembranous collagenous colitis
Yuan et al, 2003
10 cases – only one associated with CDT. Little evidence of a drug association
Yuan et al 2003
? pseudomembranous changes are part of the spectrum of CC:
?? toxin-mediated, ?? ischaemia-mediated

26. Microscopic colitis – ‘new types’
triumvirate:
eosinophils, enhanced apoptosis &
mild melanosis
drugs, especially NSAIDs
eosinophils alone
NSAIDs
gold therapy
others to come

27. Focal active colitis
focal cryptitis is an alternative name for this phenomenon
traditional pathological teaching has promulgated the view that this feature was a moderately good predictor of a diagnosis of Crohn’s disease, especially in the differential diagnosis from ulcerative colitis
but perhaps more in association with other features of chronic inflammatory bowel disease
world literature review found that ‘focal cryptitis’ to be amongst the most powerful histological parameters for the diagnosis of colorectal Crohn’s disease on biopsy material
Jenkins et al, 1997;
BSG Inflammatory Bowel Disease Pathology Initiative

28. Focal active colitis (FAC)
term used to describe isolated finding of neutrophilic crypt injury
histological features:
single/multiple foci of cryptitis
single discrete crypt abscess
multiple crypt abscesses
no significant chronic inflammation
Greenson et al, 1997

29. Focal active colitis 45% patients immunosuppressed, 40% taking NSAIDs
follow-up (1-74 months, mean = 25 maths)
acute self-limited infectious colitis (45%)
incidental finding (25%)
irritable bowel syndrome (14%)
ischaemia (10%)
antibiotic associated colitis (5%)
no patient developed CIBD
Greenson et al, 1997

30. Focal active colitis infective/ self-limited drugs IBS incidental CIBD
Greenson et al, 1997
USA
42 cases
adults
45%
14%
(NSAIDS and Abs)
26%
Volk et al,
1998
31 cases
48% ?
10% ischaemic colitis
29%
13%
all CD
Xin et al, 2003
children
31% 0%
27.6%
8 CD;
1 UC

31. Not to be outdone
prospective, unselected series from routine practice of one specialist gastrointestinal pathologist (NAS) in a single large general hospital (GRH, UK)
prospective patient accrual initiated in 1994 and terminated in 2004
approved by the Glos Research Ethics Committee (ref 05/Q2005/70)
full written consent & questionnaire, specifically designed, in which gastrointestinal symptoms, drug history and full medical history were documented
only those consenting & fully completing questionnaires included
hospital records & study questionnaires analysed independently for:
patient symptoms, drug history, microbiological findings
endoscopic findings (including preparation)
follow up, especially subsequent endoscopic & histopathological analysis for potential inflammatory bowel disease (IBD), & final outcome

32. Material and methods: pathology
FAC defined as neutrophil-mediated crypt epithelial injury involving at least one crypt and less than 50% of the biopsy specimen
biopsies diagnosed as FAC were reviewed independently by two experienced pathologists (SMA and JS)
if disagreement between the two pathologists, a third specialist gastrointestinal pathologist (NAS) mediated for a majority assessment of the pathology
biopsies excluded if chronic inflammation, granulomas or crypt architectural abnormalities or if previous diagnosis of CIBD or any other specific diagnosis
site(s) of involvement in the colorectum, amount of neutrophil crypt activity, position of PMNs in the crypt(s), number of crypt abscesses, PMNs in lamina propria, association of inflamed crypts to lympho-glandular complexes, basal FAC, crypt apoptosis, sub-epithelial apoptosis & melanosis coli

33. Results originally 145 cases fulfilled criteria for a diagnosis of FAC
only in 90 cases (62.1%) was full written consent achieved with full completion of study questionnaires, despite three rounds of letters and telephone enquiries to those giving full written consent but not returning questionnaires
? potential to introduce bias

34. Results demography 90 patients: 31M; 59F
age mean years; age range was 15 to 84 years
follow-up 2 months to 15 years with a mean of months
symptoms diarrhoea alone in 39 (43.3%); diarrhoea and pain in 18 (20%);
altered bowel habit in 12 (13.3%); constipation (1 patient);
diarrhoea and bleeding (2); diarrhoea, bleeding and pain (4);
iron deficiency anaemia (4); bleeding (5); bleeding and pain (2);
asymptomatic (3)
preparation 44 patients (50.6%) Fleet phospho-soda®
31 (35.6%) oral Klean Prep® (polyethylene glycol)
12 (13.8%) phosphate enema preparations
endoscopy 20 patients (22.2%) mild, non-specific changes;
70 (77.7%) normal, incidental polyps or diverticular disease

35. Results: pathology
no statistically significant differences between the five clinical categories of FAC with:
age, sex or other demographic feature
number and site of affected biopsies
number of crypts involved
percentage of crypt involvement in most affected biopsy
percentage of crypt involvement in all biopsies
number of crypt abscesses
presence of polymorphs in the lamina propria
association of inflamed crypts to LGCs
subepithelial apoptosis
melanosis coli

36. Results only significant correlations in ‘Drugs’ clinical category
crypt apoptosis strongly associated with drugs
drugs and ‘basal FAC’:
6 of 11 patients (vs 15 of 79 outwith BFAC group)
χ2 = 6.51, df = 1, p=0.011

37. Basal focal active colitis
10 cases of ‘basal FAC’
diffuse basal involvement of crypts by neutrophils with enhanced apoptosis
strongly associated with drugs, especially NSAIDs
? relatively specific abnormality, more likely associated with drug therapy than FAC in general
similar to ‘apoptotic colopathy’
McKenna et al, 1999

38. Results 14 patients with CIBD
infective/
self-limited
drugs
IBS
incidental
CIBD
Shetty et al, 2011 UK
90 cases adults
19%
24%
NSAIDS and Abs
33% 8%
16%
10 CD, 2 UC, 2 IBDU
14 patients with CIBD
10: Crohn’s disease (5 colorectum only; 3 ileum and colorectum; two colorectum and anus; one colon and duodenum)
2: IBDU
2: ulcerative colitis with characteristic endoscopic & histological findings affecting at least the rectum
time between FAC diagnosis & subsequent CIBD diagnosis: 18m to 6 years
no clinical or histopathological feature predicted ultimate diagnosis of CIBD type

39. infective/
self-limited
drugs
IBS
incidental
CIBD
Greenson et al, 1997
USA
42 cases
adults
45%
14%
(NSAIDS and Abs)
26%
Volk et al,
1998
31 cases
48% ?
10% ischaemic colitis
29%
13%
all CD
Xin et al, 2003
children
31% 0%
27.6%
8 CD;
1 UC
Shetty
et al,
2011 UK
90 cases adults
19%
24%
33% 8%
16%
10 CD;
2 UC;

40. Focal active colitis: discussion
the largest series of the four in the world literature
representing almost as many cases as the other three put together
only prospective and unselected study
FAC not an uncommon diagnosis in pathological practice
about 15 cases per year diagnosed in this single busy gastro-intestinal pathological practice
FAC will be diagnosed about 50 times per year in the average ‘general hospital’ practice
diagnosis more often in women, especially those eventually with CIBD
female predominance not seen in two studies but, in Greenson’s original study, 63% of the patients were female

41. Focal active colitis: discussion
? associated chronic inflammatory change in addition to FAC
may be difficult: ? normal round cell infiltrate of the lamina propria.
our study and those of Greenson: the changes represent ‘pure’ FAC
Volk study: eosinophils in 39% of cases and infiltrates of plasma cells in 35% of cases
apples and pears

42. Focal active colitis: discussion
demonstration of FAC may be incidental to the ultimate diagnosis
not considered that FAC might be a particular histopathological feature of IBS
reasonable to presume, as others have, that, if resolution of symptoms after cessation of a drug, then FAC can be attributed to an effect of the drug
demonstration of FAC may, in some cases, be incidental to the final diagnosis of CIBD
less likely for those cases of Crohn’s disease as FAC, in combination with other more chronic pathological features, is characteristic of the disease
two UC cases: FAC may be incidental to the ultimate diagnosis but, given the close proximity in time of initial symptoms, the diagnosis of FAC and the ultimate diagnosis of UC, it would seem likely that the three are directly related
parallels with diverticular colitis preceding classical UC

43. Focal active colitis: discussion
no pathological feature shown to select patients more likely to be placed in a particular diagnostic category
more extensive FAC likely to presage CIBD but not in this study
right colonic FAC may favour a drug-induced FAC as higher concentrations of the drug(s) (Warren BF, personal communication) but not in this study
infection, especially bacterial, is a prevalent cause of FAC in all four studies
in our series, isolation of pathogens unusual with only 2 patients positive for campylobacter jejuni by standard microbiological methodology
more sophisticated microbiological analysis, by PCR, can show higher rates of bacterial demonstration, specifically campylobacter, in FAC patient groups
Lamps et al, 2006

44. FAC becoming Crohn’s disease: this month’s case
23F. Initial diarrhoea. Normal colonoscopy including TI.
Six months later: worse symptoms with
endoscopic TI disease

45. A touch of reality ? Henry D Appelman
“my approach to all GI biopsies is to ignore small inflammatory things, since they are not specific diseases and they mean nothing to clinicians, unless the report is accompanied by a long, long comment explaining what these tiny insignificant things mean.”
“but don’t tell Joel – you’ll get me into trouble”
Henry D Appelman

46. Microscopic colitis: take home messages
microscopic colitis is common and is seen more and more often
we are seeing new patterns of disease in microscopic colitis
collagenous colitis is much more likely to be seen and recognised in right and transverse colonic biopsies and is more likely to be associated with endoscopic abnormality
drugs are an important cause and we do not yet know the proportion of cases of drug-induced diarrhoea that MC is responsible for
highly variable response to treatments and natural history – from complete remission (including on insult removal) to chronic relapsing disorder lasting for years refractory to most treatment

47. Focal active colitis: take home messages
FAC may be a more significant predictor of CIBD than the literature would indicate
up to half of all the patients have self-limited disease (likely infective)
strong but variable association with drugs (NSAIDs, PPIs & antibiotics) in adults, especially with basal FAC
up to 15% (higher in children) will have CIBD, more commonly CD
FAC is more important in predicting CIBD when combined with other features
FAC is a relatively common feature in routine gastrointestinal pathological practice and recent studies provide a clearer understanding of its clinical significance