the patient celiac

Celiac Disease Pathology

24 comments January 13, 2015

Dr. John Hart gave a lecture about the pathology of celiac disease during the celiac preceptorship that I attended at the University of Chicago last month. Dr. Hart is one of the world’s experts in this field. Pathology encompasses the abnormal findings that can be seen on duodenal (small bowel) biopsy in patients with celiac disease.  As a disclaimer, I have not really studied pathology since my first two years of medical school (1999-2001). Nor did I ever imagine that I'd be writing about it...

Dr. Hart started his lecture by describing the difference between the “classical” biopsy findings v. the “new” biopsy findings in celiac disease.

Classic celiac disease findings on biopsy include total villous atrophy (flattening, or blunting, of the villi throughout entire duodenum), inflammatory cells, increased intraepithelial lymphocytes (IELs), and elongated crypts.

But, it has been shown in recent years that patients with celiac disease can have totally normal looking bowel mucosa (no villous atrophy) with increased IELs only (Marsh stage 1). In the past, these Marsh stage 1 patients would not have been diagnosed with celiac disease.

Dr. Hart stated that patients with abnormally high celiac antibodies (TTG IgA) and Marsh Stage 1 findings (increased IELs) have either celiac disease or Crohn’s disease. The anti-endomysial antibody can be used to differentiate between the two--it will be elevated in cases of celiac and normal in Crohn’s. There are no other diseases that would cause an elevated TTG IgA and a Marsh 1 picture on small bowel biopsy.

Many biopsies for celiac disease are done incorrectly. At least 5 tissue samples must be obtained during biopsy.  One biopsy should be from the duodenal bulb and 4 should be from the distal duodenum.  In 2% of cases, the damage from celiac disease is in the duodenal bulb only (so if this location is not biopsied, the diagnosis of celiac can be missed).

Increased IELs, by themselves, can be seen in many diseases in addition to celiac disease. The differential diagnosis for increased IELs includes Crohn’s Disease, Giardia infection, small bowel bacterial overgrowth (SIBO), H pylori duodenitis, and use of NSAIDS (class of drugs that includes ibuprofen and naproxen).

In addition, certain medication and other diseases can cause villous blunting that mimics “classic” celiac disease. The main culprit is olmesartan, a blood pressure medication.  Losartan and mycophenolate are others.  Diseases that cause villous blunting include common variable immunodeficiency (CVID) and autoimmune enteropathy. Dr. Hart suspects that many cases of seronegative celiac disease (normal celiac antibody levels but abnormal biopsy with villous blunting) are related to medications.  He point blank stated that seronegative celiac disease should be a diagnosis of last resort.

At the end of the lecture I asked Dr. Hart if there is any window of time that an accurate biopsy can be obtained after a patient starts on a gluten-free diet, without having to undergo a gluten challenge. His answer was that is probably okay to do a biopsy within 2 weeks, with the caveat that the waters can still be “muddied” at this point.  This is the best answer that I have ever received to this question and I appreciated that he took the time to answer it.

The take-home message is that there are many patients with celiac disease who may have mild findings on biopsy and that villous blunting is no longer needed for diagnosis of celiac.  It is also important to make sure that one's biopsy is done correctly, as, sadly, many are not. As an aside, before I had my daughter's biopsy performed in June, I confirmed that her GI doctor was going to take enough samples and include the duodenal bulb.  He did not mind me asking this at all. At this point he had no idea that I was a doctor, nor did he know that I had this page.

As always, feel free to ask questions, comment, share your story, etc.  I am a bit backlogged on my email right now, so if you do email (which you are welcome to), it may take up to 2 weeks to hear back from me. Thanks for understanding.

In reply to J Wilson.
Hi J,

I’m intrigued about the association between chronic giardia and an elevated TTG IgA because I was unaware of it and have never heard mention of it before now. I’d greatly appreciate if you have any resources to share regarding this association.
Thanks so much for your help.

7/21/2016 4:45:18 PM
J Wilson
I read with this interest this post.

Im not sure about this statement “There are no other diseases that would cause an elevated TTG IgA and a Marsh 1 picture on small bowel biopsy.”

As an example chronic Giardia is thought to cause an elevated TTG iGA count as well as increased IELS and Villous atrophy.
7/21/2016 4:44:50 PM
In reply to Naomi Levinson.
Hi Naomi,
Thank you for writing. I have not encountered anyone with the combo of DH and serum IgA deficiency, but it seems entirely possible, as 3-5% of those with celiac are IgA deficient.
I actually think that the group at the Univ of Chicago, led by Dr. Guandalini, might be interested to learn about you. You can reach them through their celiac center’s website. Because I think you sound like you’d make a great case study for others to learn from :)
Thanks for writing!
7/21/2016 4:44:09 PM
Naomi Levinson
This is very interesting- my celiac diagnosis was from anti-TTG-IgG >250 (ref range >15!) followed by an endoscopy that showed no significant villi damage but very high IELs. I have no stomach aches ever – but I had a sudden onset of Dermatitis Herpetiformis which led me to celiac testing. I’m IgA deficient so my anti-TTG-IgA was zero and I have had FIVE skin biopsies negative for DH – even though it is clearly DH. I’m on dapsone and doing much better and after 9 months strictly GF my anti-TTG-IgG levels were at 25! So still positive with NO gluten ingested for 9 months. Needless to say I can’t go off dapsone yet. My question to you is: have you ever heard of anyone with DH who is IgA deficient? Have you ever heard of a DH skin biopsy that looks for IgG deposits instead of IgA? I feel like there may be many other missed cases of DH due to IgA deficiency. Thank you for your time. I am very lucky I found a gastroenterologist who diagnosed me as celiac with just high IELs and positive serology. Many people are my so lucky to get answers.
7/21/2016 4:42:59 PM
In reply to Juanita Martin.
Hi Juanita,
It’s really nice to meet you and I am so happy to learn that you are feeling so much better on the gluten-free diet. It does take a while to transition, but I can assure you that you will eventually find GF breads, pastas, rolls, pizza crusts that your whole family will eat (it just takes a little trial and error).
Please let me know if you have questions as you navigate your GF journey, and thanks so much for reading and commenting.
7/21/2016 4:41:59 PM
Juanita Martin
Hi Jess,
I recently had a EGD for worsening reflux symptoms. The EGD confirmed I have GERD, hiatal hernia, and the pathology report findings read “increased intraepithelial lymphocytes with preserved villous architecture”. My GI doctor is treating me for Celiac despite a negative serum celiac panel and since beginning my gluten free life style I cannot believe how much better I feel. I did not realize that I felt “bad” until recently. I believe the biggest challenge has been coming up with meals that everyone at home will eat because bread has always been a staple in our home. The fact that I came across the Gluten-Free Living magazine and your article is like a God send because you have answered many of the questions I had. Thank you so much for advocating for “The Patient Celiac”!!
7/21/2016 4:40:29 PM
In reply to Danny.
I hope you are able to find some answers Danny. Please keep me updated if you get a chance!
7/21/2016 4:39:37 PM
In reply to Danny.
I set up an appointment with my doctor and explained everything to him. He order a blood test again, and referred my to a GI doc. I should get the test results early next week. We’ll see what they show.
7/21/2016 4:39:14 PM
To start off, I am not looking for a diagnosis. My wife and I are trying to figure out some gluten related issues with one of our children. I decided to look back through copies of MY medical records to see if there was any history of it. Lo and behold there are some questionable results from tests performed on me as a child and as an infant. When I was 5 I had a small bowel biopsy. The results stated:

“The specemin consists of a very superficial biopsy segment of small bowel. For the most part, the villi are typically elongated and delicate. However, there are foci of villous blunting. This blunting is truly focal and not striking. No unusual inflammatory infiltrate is observed, and the histologic appearance of the epithelium is normal. No micro-organisms are identified. Although there is focal blunting of intestinal villi, this is quantitatively insufficient for a diagnosis of Celiac disease.”

Looking back further, when I was a week shy of 6 months old, my IgG, IgA and IgM levels were 320, 52 and 135 mg/dl respectively. My IgE was 36 which is right around mean +2 SD. At that time, the serum levels that were acceptable were much broader than they are now. Of course, I had to play “internet doctor to get an idea of what all of that means. According to recent guidlines, the results of all of those Ig tests suggest that I may be Celiac, or at the very least gluten intolerant. With that being said… assuming that gluten consumption has not changed much over the course of my life, do IgG, IgA, IgM, and IgE levels change over the course of one’s life? Would it be worth getting tested as an adult, 36 years later? Would it possibly give any insight on the gluten issues that my son has? Any info or ideas would be much appreciated. Thanks for your time.
7/21/2016 4:38:21 PM
In reply to Jess.
Thanks so much for the reply! Aw darn, that’s what I was scared of. I will definitely look into that!
7/21/2016 4:18:07 PM
In reply to Elizabeth.
Hi Elizabeth,
My understanding is that you have to be eating a decent gluten load in order to have elevated antibodies and overt small bowel changes after being strictly GF for quite a while (ie. that cross contamination may not cause enough damage to show up on testing). That being said, it sounds like it’s definitely worthwhile to have the celiac testing repeated, and to then try to figure out if you have another disease process going on. As you can see in the comments above, mast cell activation syndrome (MCAS, or MCAD) is a secondary diagnosis that many of us are developing in addition to celiac, and it can cause IBS-type symptoms that can mimic cross-contamination.
7/21/2016 4:17:45 PM
In reply to cathy.
Hi Cathy,
I hope that you are able to find some answers. I have connected with an NP with celiac through this page who is working on some of the research on Olmesartan and celiac disease. I can try to connect you two via email if you’d like.
Please let me know how your testing for MCAD goes. My quality of life improved a ton when i started on a regimen of antihistamines, cromolyn, and quercetin back in 2013.
7/21/2016 4:17:23 PM
In reply to Meghan.
Hi Meghan,
Thank you so much for referring people to my blog–it helps to know that there are people out there who are reading it!
I hope that you are able to get some answers about your recurrent symptoms. In my case, I had a bunch of bizarre IBS-type and other symptoms pop up at my 3y GF mark from mast cell activation syndrome.
7/21/2016 4:17:05 PM
In reply to Meghan.
I’m in the same boat, I had my baby 7 months ago and feel just like I did before I stopped eating gluten. Even all my personal products are gluten free, 4 years of health and now this happens. So strange!
7/21/2016 4:16:28 PM
Thanks for this useful info! my only question is, I know it’s recommended to eat the half slice of bread a day for 6 weeks and stuff, but I have seen people discussing positive test results brought on just by getting cross contaminated. Any idea of how likely this is? I know it probably varies from person to person but I’m trying to figure out what’s going on with me… I think I’ve been getting cross contaminated but my doctor wonders if I might have another disease in addition to celiac, and is about to run a celiac panel on me again to see if it picks up anything. I’m wondering if it’s negative if that means I’m probably not getting CCed or if it’s just not something they’ll be able to tell. :(
7/21/2016 4:16:07 PM
Very curious about the effects of olmesartan because I took that drug 4 times daily for years.
I do have a gluten sensitivity that existed prior to olmesartan and I am being tested for MCAD now.
I have many of the conditions related to MCAD. Small doses of prednisone allowed me to eat and to breathe but now that I have discontinued the prednisone those symptoms are returning.
I am doing some of the tests now including tryptase, histamine, prostaglandin. So, I don’t want to take any meds that will interfere with test results. These symptoms are quite uncomfortable and I hope to find something that will be effective, maybe the claritin, maybe something else and I need it soon.
7/21/2016 4:15:32 PM
In reply to Jess.
My previous blood test had come back a 12 (general surgeon performed it as a favor) with a negative bring <4 and a weak positive being =4-10. We assumed that was a positive and no scope was necessary. That was done after I had been off of all gluten except a communion wafer the prior Saturday and the blood was drawn Wednesday or Thursday. I am only seeing a GI now (two years later) due to a return of symptoms postpartum despite maintaining a strict gf lifestyle.
7/21/2016 4:15:09 PM
In reply to Jess.
Thanks for the reply Jess! The GI suggested I only needed to eat it 24 hrs prior to test prep and I wasn’t comfortable with that number given all I had read. Thank you for your blog and ask the info you provide! I have sent many people your way and have been able to help people with all the studies you have presented.
7/21/2016 4:14:48 PM
In reply to Erica.
Hi Erica,
I am going to have to check on that for you because I don’t believe that he provided references at the end of the lecture. I wrote my post from my notes, but can go back to the PP slides to check. I know that this does reflect information that was presented at the ICDS in Sept. 2013 as well.
So, I’ll let you know if I can actually find anything published about this.
7/21/2016 4:14:29 PM
In reply to Meghan.
Hi Meghan,
It’s good to see you. The consensus at the conference was that a “gluten challenge” in adults consists of eating at least 1/2 slice of bread for 2 weeks prior to a small bowel biopsy (and 6 weeks prior to celiac blood antibody testing). I am pretty sure that this comes from a study that Dr. Leffler published sometime in the last 24 months.
I hope that your scope and biopsy goes well!
7/21/2016 4:13:52 PM
Melissa Miller
In reply to Meghan.
My GI doc suggested a 6 week “challenge” with gluten equal to 1 slice of bread a day. This was 7 years ago though.
7/21/2016 4:13:08 PM
Did he give any more definitive information for how long a gluten challenge should be prior to biopsies? I had a positive TTG IgA but no follow up biopsy add I had been gluten free for a while prior to the results getting back. I am now seeing a new GI for persistent symptoms and he would like to do a follow up scope and biopsy for a diagnosis and to look for reasons for persistent symptoms.
7/21/2016 4:12:34 PM
*personal experience -sorry, tired eyes :)
7/21/2016 4:12:04 PM
Jess-this post answers so many “grey area” questions with regard to my personal Thank you so much for sharing. Did he publish anything with regard to this information? (especially the Marsh I/IEL-Chron’s/Celiac statements).
7/21/2016 4:11:03 PM
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