1. Microscopic Colitis: The Past, Present, and Future
Nicole Gentile, MD
Chief Gastroenterology Fellow
June 16, 2017

2. Disclosures
None

3. Case
68 year old female with history of type II DM (diet controlled) presents to your office for evaluation of non bloody diarrhea for the past 2 years.
The diarrhea waxes and wanes
10 pound weight loss/2 years
4-5 watery non bloody stools/day
occasional nocturnal BM (few episodes of fecal incontinence)
Saw a GI physician 2 years ago for a routine screening colonoscopy (normal)
diagnosed with IBS
Takes Metamucil and occasionally takes loperamide (helps).
Comes to your office for a second opinion

4. Case Continued
Family history is negative for inflammatory bowel disease, Celiac disease, and colon cancer.
No new medications
Vitals are stable.
Physical exam is unremarkable.

5. Patients often see their internists first prior to presenting to GI for chronic diarrhea.
This cartoon sums up how many of our patients feel. In the words of Dr. Goldstein diarrhea is “the snot of the GI tract.”

6. Inflammatory Bowel Disease Infectious
Osmotic
Lactose Intolerance
Sorbitol
Surgery
Post-cholecystectomy
Bile acid Diarrhea
Short bowel syndrome
Ischemia
Ishcemic Coltiis
Chronic Mesenteric Ischemia
Inflammatory Bowel Disease
Infectious
Bacteria
Parasites (Giardia)
Malabsorptive
Celiac Disease
Chronic pancreatitis
Secretory
Carcinoid Syndrome
VIPoma
Id like to take a moment to address the different categories for chronic diarrhea as treatment differs depending on what is causing the diarrhea.
But Id like to remind you that often times the diagnosis is in the history.
Discuss causes listed above.
Functional
Irritable Bowel Syndrome
Prior radiation
Radiation Colitis
Medications
Malignancy
Lymphoma

7. Chronic Diarrhea: Indications for Colonoscopy
Age >50
Family history of colon cancer
Change in bowel habits
Abnormal imaging
Abnormal fecal occult blood test, fecal immunohistochemical test (FIT), Stool DNA (in the setting of colon cancer screening)
Blood in stool
When we are discussing chronic diarrhea not everyone needs an immediate colonoscopy. Lets review the red flags where colonoscopy is indicated.

8. Case
Crohn’s Disease
Terminal ileum ulceration
Deep Ulcerations
Fistula
Lets take a moment to review what we see endoscopic ally with different patient populations
Middle Picture: Deep serpinginous ulcerations and cobllestones
Recto vaginal fistula
Crohn’s colitis:
Transmural
Discontinuous
“skip lesions”
“cobblestoning
Last picture:
Entero-entero
Enterovesical
- Rectovaginal
This is a patient who presents with diarrhea, urgency, weight loss, nocturnal stools, aphthous ulcerations
Baumgart DC. Lancet 2007; 369: 1641–57

9. Ulcerative Colitis Case
Rectum
Descending Colon
Normal Terminal ileum
NEED TO FIND PICTURES
Mild-moderate - Granular - Loss of vascular pattern
Moderate-severe - Pseudopolyps - Friability / bleeding - Loss of vascular pattern
This patient presents with > 15 small bloody stools per day, nocturnal bowel movements, weight loss

10. Case
Normal
Appendiceal Orfice
Transverse Colon
Descending Colon
This is a patient with no family history of colon cancer or change in bowel movements who presents for a screening colonoscopy

11. Case
Appendiceal Orfice
Transverse Colon
Descending Colon
This is a female age 65 who presents with 2 years of watery diarrhea with now fecal incontinence, our case

12. What is the endoscopic difference between the last 2 cases?
Who can tell me the difference between the screening colonoscopy and our patient? Let me show you again….

13. Normal Endoscopic Appearance ≠ Normal Colonoscopy
A normal endoscopic appearance on a colonoscopy does not mean someone has a normal colonoscopy.
You need to take random biopsies which should not surprise you that this is how we diagnose MC

14. Back to Our Case Answer:
Obtain the colonoscopy report to see if random biopsies were taken
Getting back to our patient I would recommend obtaining the colonscopy report to see if any random biopsies were taken as well as check stool studies at this time
As I just showed you endoscopically the mucosa looks normal. Therefore if you are not thinking about MC…looking for MC with biopsy…then you will miss a treatable disease.

15. Delayed Diagnosis NorthShore MC registry: n= 91
Average delay in dx: 30.5 months
Diarrhea as a chief complaint was documented approximately 3.7 times prior to MC diagnosis.
Conclusion: Shared lack of awareness between providers (delayed referrals) and patients (infrequent reporting).
From internist to Gastroenterologist how long is care transitioned before the diagnosis is made. As you can see diarrhea as the chief complaint gets 3.7 times more visits for the point to come across that the diarrhea is causing issues and even longer on average 30.5 months before the colonoscopy is done and diagnosis is made.
How do we know this is an orphan diagnosis that gets missed.
Dr Yen has the largest prospective registry of patients with microscopic colitis to date. He evaluated 91 patients from symptom presentation to final diagnosis of MC and concluded that there was a delay in diagnosis of 30.5 months. Now imagine these are patients with incontinence, nocturnal stools, and poor quality of life.
Females (n=69) 35.9 months vs. males (n=17) months.
The number of diarrheal complaints did not differ in patients with longer versus shorter duration of diarrheal symptoms.
Yen EF et al. DDW 2016: S403

16. This is NOT IBS!
It is ok to talk about Irritable bowel syndrome in the younger population, but in the elderly female with chronic diarrhea be ware of the mimickers you must.

17. Microscopic Colitis Lymphocytic Colitis (LC) Collagenous Colitis (CC)
Similar clinical presentation
Similar treatment
Differ histologically
When we speak of microscopic colitis we are referring to 2 entities that are clinically similar but different histologically
Pardi DS. Am J Gastroenterol 2017; 112:78-85.

18. History of microscopic colitis
2003
2002
1st RCT of Collagenous colitis
2000-
Immunology, pathophysiology.
1995
Epidemiology, natural history
1989
If we look back at the history of Microscopic colitis you can see that our awareness and knowledge is evolving. Even though we heard about it in 1980, it is not until the early 2000s that we start to see randomized control trials.
1st report of Lymphocytic colitis
1980
1st report of Microscopic colitis
Microscopic colitis manuscripts
1976
1st report of Collagenous colitis
Used with permission from Eugene Yen.

19. Epidemiology of MC Aim:
Ascertain incidence trends and the overall prevalence of microscopic colitis in a population-based study
Methods:
Rochester Epidemiology Project
Residents of Olmsted County, MN, who were diagnosed with CC or LC from January 1, 2002, through December 31, 2010, based on biopsy results and the presence of diarrhea
Gentile et al. CGH May;12(5):

20. Epidemiology of MC Results: N = 182 Mean age at diagnosis = 65.8 years
76.4% women
This is consistent with the literature in studies in europe and spain and our NorthShore experience– this is a disease of older patients and mainly females
Gentile, et al. CGH May;12(5):

21. Changes in incidence over time were not significant (P=0.63)
Age and sex adjusted Incidence of MC over time in residents of Olmsted County, MN, 2002–2010
12.9 per 100,000 person years (95% CI, ) for Crohn’s disease
12.5 per 100,000 person years (95% CI, ) for Ulcerative Colitis
We found that at the end of the study period the incidence of MC has exceeded that of IBD for Olmstead County
Changes in incidence over time were not significant (P=0.63)
Gentile, et al. CGH May;12(5):
Ingle, et al. Gastro (4 Supp 2):A19-20

22. Microscopic colitis vs. other forms of IBD
EPIMAD registry
Population-based (Northern France)
Compared UC, Crohn’s and MC incidence
Fumery M et al. Dig Dis Sci ;62(6):

23. Epidemiology Approaching IBD
We can see that the epidemiology of MC is truly approaching that of Inflammatory bowel disease
Gentile N, Yen E. Dig Dis Sci (2017) 62:1394–1395.

24. Symptoms Same for Lymphocytic and Collagenous Colitis
Mild to severe watery non bloody stools
Incontinence
Urgency
Nocturnal stools
Weight loss
Abdominal pain (not common)
Common cause of chronic diarrhea in elderly females
May be misdiagnosed as IBS resulting in delayed diagnosis
Watery non bloody stools can be mild to severe causing dehydration
Pardi DS. Am J Gastroenterol 2017; 112:78-85.

25. Association with Autoimmune Disease
Diabetes
Thyroid disease
Psoriasis
Celiac disease (CD)
You may be asking … what is Microscopic colitis. Is it a form of Inflammatory bowel disease…will it become inflammatory bowel disease. We can obtain hints by looking at the autoimmune diseases that Microscopic Colitis is associated with
Pardi DS. Am J Gastroenterol 2017; 112:78-85.

26. Association with Celiac Disease (CD)
Prevalence of CD in patients with MC ranges from 2% to 9%
In patients with MC with refractory diarrhea, recommend checking for CD
Consider small bowel biopsies if you are suspicious for celiac disease in MC patients
Concern that celiac serologies are less sensitive in patients with MC
Olesen M et al. Gut. 2004; 53:
Bohr et al. Gut 1996; 39:
Pardi et al. Am J Gastroenterol 2002;97:

27. Are there environmental factors such as smoking that impact disease?
We commonly counsel against smoking in patients with Inflammatory bowel disease
This relationship is well established with:
Disease onset
Recurrence after surgery
Poor response to medical therapy
Parkes et al. J Crohns Colitis Aug;8(8):

28. Smoking and MC Case Control Study (NorthShore) Cases: 340 with MC
Control group:
340 age and gender matched patients who underwent colonoscopy without diarrhea
Conclusion:
Cigarette smoking is a risk factor for the development of MC regardless of type of MC or gender
Greater association in current smokers (ADD OR)
We can answer this question in regards to the impact of smoking on microscopic colitis by our own Dr. Eugene Yen.
Yen EF et al. Inflamm Bowel Dis. 2012;18:

29. Medication exposure and the risk of microscopic colitis: Results from a prospective trial
185 patients undergoing colonoscopy with planned biopsy for suspicion of MC
Prior to procedure, patients surveyed on regular medication use
Results:
After controlling for age and gender, any aspirin/NSAID was a strong independent predictor of MC (OR 3.75, 95% CI )
Are NSAIDS causative? Should we be stopping them?
SAY Definition: At least three times per week for at least 2 weeks just prior to the exam
Association and not causation
There was no signal with PPIs
Dr Yens prospective research is suggestive of a relationship. However to truly define this question patients would need to be prospectively randomized to no nsaids and continuation of nsaids and follwed.
Based on his study, we have enough evidence to withdraw NAIDS as we believe that alters diesease progression
Yen at al. Presented at DDW 2017.

30. How Do You Make the Diagnosis?
Is it a clinical diagnosis?
Is it a histologic diagnosis?
Is it one of the above, both, neither?

31. Endoscopic Appearance
It is not diagnostic as with UC or Crohn’s disease
Normal endoscopic appearance
In order to find it we must look
for it with random biopsies
taken from the colon

32. Histology Lymphocytic Colitis Collagenous Colitis
>20 intra-epithelial lymphocytes/100 surface epithelial cells
Collagenous Colitis
Presence of a collagen band (>7 μm)
Normal is < 5 μm
Histologically they may have overlapping features but treatment will be the same
Pardi DS. Am J Gastroenterol 2017; 112:78-85.

33. Our Approach to Treatment
Mild disease
≤ 5 watery BMs per day
No nocturnal BMs, weight loss, incontinence
Moderate to severe disease
6 or more watery stools per day
Presence of nocturnal BMs, incontinence, weight loss
In our experience

34. Mild MC Smoking cessation Review meds: NSAIDs Anti-diarrheals:
Loperamide, bismuth subsalicylate
Cholestyramine
60% response in retrospective studies
Bile-acid malabsorption a potential mechanism of MC
40% of MC patients have abnormal histology in TI
Our goal with mild disease is to try to avoid corticosteroids
Fine KD et al. Gastroenterology. 1999;116:G3825.

35. Bismuth Subsalicylate: Response by Dose
Number of Tablets
No Response
Response 6
36%
64% 8 8%
92% 9
20%
80%
Median time to recurrence = 12.5 weeks
I am privileged to share with you data on bismuth subsalicylate based on studies while I was at Mayo.
Similar to the data I already showed you although there is a high response we know there is also a short time to recurrence.
The problem is still disease recurrence
(I grouped partial and complete response together)
Gentile et al. Presented at DDW 2014.

36. Moderate to Severe Disease
Budesonide for 8 weeks
9 mg for 4 weeks
6 mg for 2 weeks
3 mg for 2 weeks
Assess for response with each taper
May also use anti-diarrheals

37. MC and Corticosteroids
Aim:
To evaluate the outcomes of corticosteroid-treated MC in a population-based cohort
To compare these outcomes in patients treated with prednisone or budesonide for 8 weeks
Methods:
A cohort study of Olmsted County, MN residents diagnosed with LC or CC between 1986 and 2010 was performed using the Rochester Epidemiology Project
We can get a better appreciation of this answer by looking at a study I published with my colleagues at Mayo Clinic looking at corticosteroids for disease treatment, which we commonly use with IBD.
Gentile, et al. Am J Gastro Feb;108(2):256-9.

38. Patient Characteristics
Say this:
Go in order
80 treated with corticosteroids
Median age at colitis diagnosis was 66.5 years and 78.7% were female
50% had LC and 50% had collagenous colitis
Prednisone was used in 17 patients (21.2%) and budesonide in 63 (78.8%)
Gentile et al. Am J Gastroenterol 2013; 108:256–259.

39. Recurrence 70% of patients recurred after completing steroid treatment
Of those who recurred, the median time to recurrence was:
21 days for prednisone
65 days for budesonide
70.4% had a recurrence after corticosteroid discontinuation
After 397 person years of follow-up in the 73 patients with long-term data, 47 (64.4%) required maintenance with corticosteroids
The median time to recurrence after stopping prednisone was 21.0 days, which was significantly shorter than after stopping budesonide (4 days, P=0.02)
Even though there is a high rate of response to budesonide, patients are also at risk of recurrence suggestive of a chronic disease process like IBD
Gentile, et al. Am J Gastro Feb;108(2):256-9.

40. What about the patients who continue to have disease recurrence?
Some of our patients cannot taper off of budesonide
Long term treatment with budesonide at the smallest dose
Option 1 is long term maintenance with the lowest dose of budesonide that provides symptomatic relief – for some of our patients this is 3 mg daily as with patients with IBD who need long term treatment
However there are case reports to induce remission with 6 MP, azathioprine, infliximab however these are not evidenced based
We may try concomitant therapies with imodium, pepto, cholestyramine.
Like UC and Crohns recurrence rates are high and unlike IBD we do not have much evidence based literature to guide our maintenace therapies

41. MC at NorthShore: Research Goals
Disease Management
Clinical
Improved Quality of Life
Histological
MC is an understudied disease with many questions left unanswered.
Here at NorthShore through the efforts of Dr Yen and myself we seek to answre the ? Of clinical risk factors, maintenace therapies, quality of life. I decided during my fellowship that I would focus on better understanding the histology and natural history of this disease as little is known.
Currently we use histology as a diagnostic tool but much like Crohns and UC we seek to understand if there are certain histologic parameters that would help to guide disease treatment and maintenance therapy
Id like to share with you some of the results of my findings.
So what are our goals? It is 2 fold
These goals have made up the portfolio of our research studies at NorhShore
We have a prospective registry of patients with biopsy proven microscopic colitis
Our first goal is to take the clinical symptom presentation and develop predictors that will guide treatment, resolve symptoms, improve quality of life, and achieve disease remission
In addition, we feel the degree of histological damage is a more objective way of measuring disease and will be used in prospective trials.
I would like to talk to you about three studies during my fellowship that will set the groundwork for how we transition our treatment of MC.
However it is our goal at northshore to incorporate histology to see if this is predictive of response and remission
Predictors of Natural History

42. Study #1 Predicting Histologic Severity Among Pathologists in Microscopic Colitis
In my first study we looked at whether pathologists could predict histologic severity among patients with MC
We first wanted to get a better assessment of how well our pathologists when blinded could predict clinical disease severity based on histologic findings.
Gentile et al. Presented at ACG

43. Predicting Histologic Severity: Methods
3 experienced pathologists were blinded to clinical disease and diagnosis and reviewed all patients separately
Clinically, 14 patients had mild disease and 16 had severe disease
Gentile et al. Presented at ACG

44. Predicting Histologic Severity Conclusion
Overall, agreement among the pathologists was 5/14 for mild disease and 10/16 in severe disease
Overall there was great inter-observer variability
Conclusion:
Standard histologic parameters for diagnosis MC were not sensitive for predicting clinical severity
Based on simply looking at the pathology, prediction of clinical and histologic severity correlated in 5/14 for mild disease and 10/16 for severe cases
Histology is not sensitive for predicting clinical severity
….this is currently in contrast to what we use in UC and Crohns disease. The pathologists we worked with are responsible for diagnosis of the disease. Asking them to predict severity is new and a learning process as they usually are not provided clinical context when they review pathology. This was a learning process for all of us.
Gentile et al. Presented at ACG

45. Study #2 Histologic Evaluation of Disease Severity In Microscopic Colitis:
Our next study I focused on patients with both clinically mild and clinically severe disease
Gentile et al. Presented at Advances in IBD

46. Histology Pilot Study Aim
Establish histologic grading criteria that may reliably distinguish clinically mild from severe cases of MC
Not to give up, we asked questions about histology.
The first study showed that we are not as great as evaluating histologic severity overall. We decided to push ahead and look at 5 cases of clinically mild disease and compare to 5 cases of clinically severe disease to see if anything stood out
Gentile et al. Presented at Advances in IBD

47. Results Intraepithelial lymphocytosis  No
Quantity and quality of lamina propria inflammatory cell infiltrate  No
Thick abnormal collagen layer  No
Surface erosions and damage  Yes
What we found was that the above did not correlate as has what has been reported in the literature
We started to see a pattern of surface damage and erosions in the clinically severe cases but not mild cases
Gentile et al. Presented at Advances in IBD

48. Lymphocytic Colitis Resolving erosion Clinically severe disease
Resolving erosions (in the circle)
3+ intraepithelial lymphocytosis
Clinically severe disease
Surface epithelial injury with healing erosion tended to predict more severe disease activity

49. Study #3 Assessment of Histologic Disease Activity in Microscopic Colitis in Patients with Clinically Severe Disease
We lastly looked at patients with only clinically severe disease and blinded 3 pathologists to clinical information.
Gentile et al. Presented at Advances in IBD

50. Methods
7 morphologic features were assigned a numerical value from 0 to 3:
0=none, 1=mild, 2=moderate, 3=severe
Histologic features scored:
Quantification of intraepithelial lymphocytes
Quantification of intraepithelial neutrophils and or eosinophils
Lamina propria inflammation
Extent of abnormal collagen layer
Crypt architectural distortion
Separation of the superficial epithelium from the basement membrane
Surface epithelial injury including epithelial attenuation and loss of goblet cells
We asked pathologists to grade on a 0 to 3 system, with a score of 3 correlating with most severe findings
We again wanted to confirm that criteria 1-5 were not as important
Our goal was to evaluate the utility of standardized histologic features which included bullet point 6 and 7
Average age was 56 years old with 80% female
None had concomitant celiac disease, IBD, or NSAID/SSRI use
Gentile et al. Presented at Advances in IBD

51. Surface Epithelial Damage
All three pathologists aggreed that clinically severe disease correlated with histologic findings of surface epithelial damage
Gentile N. et al. AIBD CCFA 2016

52. Lymphocytic Colitis Attenuation
Resolving erosions (in the circle)
3+ intraepithelial lymphocytosis
Clinically severe disease

53. Looking to the Future…
As I join the Gastroenterology faculty, I hope to continue my work with Dr. Yen to prospectively apply our findings and address the question if clinical and histologic disease correlate and develop criteria in order to better treat our patients and taper therapies accordingly.
Say what our advantages are --- collaboration with Mayo and university of Chicago, tissue banking

54. Acknowledgement Dr Jay Goldstein Dr Eugene Yen Dr Nora Joseph
Dr Thomas Victor
Dr Curtis Hall

55. References
Pardi, Darrell. Diagnosis and Management of Microscopic Colitis. Am J Gastroenterol 2017; 112:78-85.
Gentile et al. The Epidemiology of Microscopic Colitis in Olmsted County From 2002 to 2010: A Population-Based Study. CGH. 2014;12:838–842.
Gentile, Yen. Editorial. The Incidence of Microscopic Colitis: Microscopic No More. Dig Dis Sci (2017) 62:1394–1395.
Gentile et al. Outcomes of Patients With Microscopic Colitis Treated With Corticosteroids: A Population-Based Study. Am J Gastroenterol 2013; 108:256–259.
Olesen M et al. Microscopic Colitis: A common diarrhoeal disease. An epidemiological study in Orebro, Sweden, Gut. 2004; 53:
Bohr J et al. Collagenous Colitis: A retrospective study of clinical presentation and treatment in 163 patients. Gut. 1996; 39:
Pardi et al. Lymphocytic Colitis: Clinical features, treatment, and outcomes. Am J Gastroenterol. 2002; 97:
Cotter TG et al. Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study. Gut 2016;0:1–6. doi: /gutjnl
Yen EF et al. Current and past cigarette smoking significantly increase risk for microscopic colitis. Inflamm Bowel Dis Oct;18(10):
Fumery M et al. Incidence, Clinical Presentation, and Associated Factors of Microscopic Colitis in Northern France: A Population-Based Study. Dig Dis Sci Jun;62(6):
Parkes et al. Smoking in inflammatory bowel disease: impact on disease course and insights into the aetiology of its effect.J Crohns Colitis Aug;8(8):