Celiac Disease

Summary

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Run the List Podcast – “Celiac Disease: Approach to Diagnosis”

Hosts: Navin Kumar, with guest Dr. Sith Saker
Date: March 30, 2026

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Episode Overview

This episode dives into the high-yield topic of celiac disease, focusing specifically on the approach to its diagnosis. Joined by expert gastroenterologist Dr. Sith Saker from Brigham and Women's Hospital, the hosts dissect a typical clinical scenario, highlight key diagnostic steps, clarify pitfalls, and summarize practical pearls for internal medicine clinicians and trainees.

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Key Discussion Points & Insights

1. Initial Case Presentation & Differential Diagnosis

[03:13] Navin & Dr. Saker

• Case: 34-year-old woman with iron deficiency anemia refractory to supplements, bloating, stool changes, fatigue, and family history of type 1 diabetes.
• Physical exam: Skin pallor, mild abdominal distension, hyperactive bowel sounds.
• Dr. Saker:
  • "The first thing that comes to mind is celiac disease... The iron deficiency anemia that’s refractory to supplementation is one thing. The family history of type 1 diabetes... those would be the number one things."
  • Other considerations: SIBO, IBD (Crohn’s, UC), IBS-D.
  • Up to 3-5% of iron deficiency anemia cases have celiac disease.
  • Basic workup: CBC, TSH, celiac serologies, fecal calprotectin.

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2. Celiac Serologies: What and Why

[04:42] Dr. Saker

• Primary test: Tissue transglutaminase IgA (TTG-IgA) – best sensitivity and specificity.
• Key point: Always check total IgA alongside TTG-IgA to identify IgA deficiency.
• Quote:
  • "The important thing to know about that is that you need to also check the IgA level as well and then also need to ask if the patient is still taking gluten."

[05:55]

• If IgA deficient:
  • TTG-IgA is unreliable.
  • Switch to: IgG-based testing (TTG-IgG or deaminated gliadin peptide IgG).

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3. The Gluten-Free Patient & Genetic Testing

[07:00] Dr. Saker

• Problem: Patient already started gluten-free diet after positive serology.
• Solution:
  • Next step: HLA-DQ2 and DQ8 genetic testing.
  • If negative: Nearly rules out celiac disease.
  • If positive: Not definitive—proceed to gluten challenge for 2-4 weeks (1-3 slices of bread/day), then repeat serology/EGD.
• Quote:
  • "If negative, you can exclude celiac in these cases. If positive, you sort of still have to go down the pathway..."

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4. Endoscopic Diagnosis & Biopsy Approach

[08:20] Dr. Saker

• After positive serology (still on gluten):
  • Proceed to upper endoscopy (EGD) with multiple (≥6) duodenal biopsies.
  • Sample both duodenal bulb and (mainly) distal duodenum.
• Reason: Celiac can be patchy and more prominent in distal duodenum.
• Clinical note: Indicate biopsy sites in procedure report.

[10:14]

• Endoscopic findings: Scalloped duodenal mucosa.
• Pathology: Villous blunting, increased intraepithelial lymphocytes.

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5. Discordant Results: Positive Serology, Negative Biopsies

[09:24] Dr. Saker

• Possible explanations:
  • False-positive TTG (rare if titers high).
  • More common: False-negative biopsies due to patchy involvement.
• Next steps:
  • HLA-DQ2/DQ8 genetic testing.
  • If HLA positive: Extended gluten challenge (1-3 months, sometimes up to 6-12 months), then repeat EGD.

Quote:

• "Celiac is just so patchy and that's why we get so many biopsies from the duodenum."

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Notable Quotes & Memorable Teaching Moments

• Dr. Saker [03:13]: “Iron deficiency anemia that’s refractory to supplementation ... 3 to 5% of patients with iron deficiency anemia have celiac disease.”
• Dr. Saker [04:42]: “The big one that we’re looking at is TTG-IgA … the best combination of sensitivity and specificity for celiac disease.”
• Dr. Saker [05:55]: “If there is IgA deficiency, then the TTG-IgA is not reliable at all ... use an IgG-based test.”
• Dr. Saker [07:00]: “Luckily, we have some pretty good genes that we map to celiac ... HLA-DQ2 and DQ8.”
• Navin [08:51]: “Indicate in my procedure report that I've obtained biopsies both from the duodenal bulb and the more distal duodenum, and ... get more from the distal duodenum because that's often where the celiac disease is presenting itself.”
• Dr. Saker [09:24]: “Celiac is just so patchy and that’s why we get so many biopsies from the duodenum.”
• Dr. Saker (RTL Pearls) [11:06]:
  • “Anytime you have a patient with iron deficiency anemia, celiac disease should be something you screen for with serologies.”
  • “Always send total IgA with TTG-IgA to screen for IgA deficiency.”
  • “If there is IgA deficiency, use an IgG-based test.”
  • “In discordant results ... use HLA-DQ2, DQ8 genetic testing; negative rules out celiac.”
  • “Most important: Patients should keep eating gluten until after their diagnostic upper endoscopy.”

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Timestamps at a Glance

• [03:13]: Initial case presentation and clinical reasoning
• [04:42]: Choice and rationale behind celiac serologies
• [05:55]: Approach to IgA deficiency
• [07:00]: Handling gluten-free patients and role of genetic testing
• [08:20]: Indications and best practices for endoscopic biopsy
• [09:24]: Dealing with discordant serology/biopsy results
• [11:06]: “RTL Pearls” – summary and clinical takeaways

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Clinical Pearls (RTL Pearls from Dr. Saker, [11:06])

• Screen for celiac disease in any patient with unexplained iron deficiency anemia.
• Send both TTG-IgA and total IgA with celiac serologies.
• If IgA deficiency is present, switch to IgG-based assays (TTG-IgG, deaminated gliadin peptide IgG).
• In discordant results, HLA-DQ2/DQ8 negativity rules out celiac disease; positivity may require gluten challenge and repeated testing.
• Ensure patients keep consuming gluten until biopsy-based diagnosis is completed to maximize diagnostic accuracy.

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Key Takeaway

Always maintain a high index of suspicion for celiac disease in patients with unexplained iron deficiency anemia or chronic GI symptoms, and adhere to a systematic, evidence-based diagnostic approach—pairing serologies with thoughtful use of endoscopy, biopsy, and sometimes genetic and dietary challenge testing.

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For further detail on celiac management, stay tuned for future episodes!

Transcript

[Host]

Welcome back to Run the List, a medical education podcast in internal medicine. As a quick disclaimer, this podcast is made for educational and informational purposes only and should not be understood as medical advice under any circumstances. Before we get to the show, a quick word on the sponsors for today's episode.

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[Navin]

Welcome back to Run the List. Today we will be discussing another high yield topic for primary care and GI clinic and that is Celiac Disease. We are again so lucky to have Dr. Sith Saker joining us as our expert. Dr. Sakar is a general Gastroenterologist at the Brigham Women's Hospital and soon to be gastroenterology hospitalist who has a particular interest in medical education. Sif, thank you so much for joining us today.

[Dr. Sith Saker]

Thanks Navin. It's great to be back on the Run the List podcast and to help teach about this very important topic today with you.

[Navin]

Same here Sif. Let's go ahead and Run the list. Let's set the stage. In GI clinic, you are seeing a 34 year old healthy female with a history of iron deficiency anemia who is presenting with bloating, a change in her stool quality and fatigue. She recalls being told to start an iron supplement in the past and but that it did not improve her fatigue or her blood count. Her family history is notable for type 1 diabetes in her mother. And on exam, you know, it's skin pallor and a mildly distended abdomen with hyperactive bowel sounds and slight tenderness in the upper abdomen. Sith, given that case presentation, what differential diagnosis comes to mind and how would you approach the initial workup?

[Dr. Sith Saker]

Yeah, I think the differential is probably pretty broad with this presentation. I think the first thing that really comes to my mind would be celiac disease. A couple things really sort of stand out to me. I think the iron deficiency anemia that's refractory to supplementation is one thing. The family history of the type 1 diabetes, which increases the risk of celiac disease. And I think those that would be the number one thing that comes to my mind. Other things to consider would be things like small intestinal bacterial overgrowth, inflammatory bowel disease, Crohn's ulcerative colitis could present like this and then IBS D in general. But I think celiac is sort of at the top, especially with iron, especially when you think about 3 to 5% of patients with iron deficiency anemia have celiac disease. And then the refractory to oral supplementation, especially where celiac effects in the duodenum and the jejunum where iron is absorbed. And then, you know, some basic workup I would get would be things like cbc, tsh, celiac serologies, and then fecal calprotectin, especially to evaluate that change in her stool quality.

[Navin]

All right, so that's a great starting point. And I love the emphasis on the iron deficiency anemia that is not improving with PO iron supplementation, which suggests that there could be some issue with malabsorption. And that's kind of hinting to you that this could be celiac disease. All right, so Sith, you mentioned celiac serologies. Can you discuss specifically what serologies you send? I know we talk about them in general, but what do you specifically send and why? Are those the labs that you send?

[Dr. Sith Saker]

Yeah, I think when we send celiac serologies, the big one that we're looking at is ttg, iga. That's sort of the most, the best combination of sensitivity and specificity for celiac disease. The important thing to know about that is that you need to also check the IGA level as well and then also need to ask if the patient is still taking gluten. A lot of these patients, by the time they get to you, they've tried a lot of different dietary modifications, including stopping gluten. So it's really important to ask about if they're still consuming gluten because that can really affect the testing. Perfect.

[Navin]

I've also had the situation where a patient has gotten a positive celiac serology and then they were advised to stop eating gluten right away. And then by the time they get to GI clinic, as you mentioned, we're left in this situation where they had a positive celiac serology, but now they're on a gluten free diet. And so we'll talk about that in a bit, what we what we need to do in that case. But getting back to what you just discussed, so what happens if you send a tissue transglutaminase IGA level along with the IGA level and the IGA level comes back undetectable? What do you do with that result?

[Dr. Sith Saker]

Yeah, I think that's sort of, you know, why you send IgA because you want to make sure there's no IgA deficiency. Because if it comes back undetectable and there is deficiency, then the TTG IGA is not reliable at all. And in that case then you would use IgG trans tissue glutaminase instead. Or you can use any other sort of igg based test, sort of like a deaminated gliadin protein testing. But when it comes back and there's IgA deficiency, then you want to choose more of a route of an igg testing for it. That's sort of where I would go when it's an IGA deficiency. Okay, great.

[Navin]

So nice teaching point there. To always send the IGA level, the total IGA level, with any ttg, iga, celiac test. And then getting back to the scenario in which a patient comes to you on a gluten free diet but at some point had an elevated ttg, IGA or other celiac serology. Seth, how do you think about working up those patients who have already started gluten free diet but had a positive celiac serology as part of their workup.

[Dr. Sith Saker]

Yeah, I think the next test I really think about is sort of genetic testing. And you know, luckily we have some pretty good genes that we map to celiac and that would be HLA, DQ2 and DQ8. These are sort of really helpful, because if negative, you know, they're very, very sensitive. So if negative, you can exclude celiac in these cases. If positive is not as helpful, you sort of still have to go down the pathway, but it being negative can exclude the celiac. So if it is positive and you're in that case where they've already started a gluten free diet, then we would ask, you know, to re challenge gluten, which can be difficult for patients for at least two weeks, and then repeat serology. And gluten challenge is sort of trying to eat about one to three pieces of bread a day for sort of those two weeks or four weeks before repeating serologies or other testing, including endoscopy, which we'll talk about coming up. Excellent.

[Navin]

All right, that was super helpful to review those situations as they do come up, I'd have to say with some frequency. All right, so let's say our patient is consuming gluten and the initial labs are notable for a mild anemia. We'll say it's microcytic with a hemoglobin of 11 and the TTG IGA returns significantly elevated at 500 units per milliliter. And you did check the IGA level and that was normal. So what is the next step in diagnosis for this patient?

[Dr. Sith Saker]

Yeah, the next step is to proceed to an upper endoscopy. And it's important that the patient remains on gluten. So you can get the best sort of testing from biopsies. And you want to take duodenal biopsies multiple. We usually try to get at least six, and we want to get it both from the bulb, which is the first part of the duodenum, as well as more from the distal duodenum. And actually, celiac preferably affects the more distal duodenum. So we try to get more of our pieces from there and sort of look for things on pathology that are consistent with celiac. Perfect.

[Navin]

Seth? Yeah, that's such a good point about the biopsying approach. And so one thing I do, I know you do it as well as I indicate in my procedure report that I've obtained biopsies both from the duodenal bulb and the more distal duodenum, and like you said, to get more from the distal duodenum because that's often where the celiac disease is presenting itself. So. All right, so now some cases we will see these discordant results where the celiac serology is positive, but then the biopsies come back normal. So in those situations, Seth, what's Your approach, what are you thinking are the possibilities?

[Dr. Sith Saker]

Yeah, I think in those cases you can either have a false positive of the ttg, it's less likely, especially if the titers are high, or you more likely will get false negative biopsies because celiac is just so patchy and that's why we get so many biopsies from the duodenum. I think this is an excellent sort of use case for the genetic testing of the HLA DQ2 and DQ8. Similarly, as before, if it's negative, you can exclude celiac in these cases. If it is positive, as it most likely will be, then you can perform more intensive gluten challenge. Have them, you know, eat sort of three pieces of toast for about one to three months and then continue to eat that and then repeat the EGD after sort of about three months. And sometimes you even need them on a gluten challenge for up to 6 to 12 months before repeating the EGD. Wow.

[Navin]

So that HLA DQ2 DQA testing again comes in very handy in this discordant results scenario. All right, so Sith, that was a great review. Let's get back to our case. So our patient undergoes an upper endoscopy while continuing to consume gluten. The endoscopist notes a scalloped appearance of the duodenal mucosa, which is suggestive of celiac disease. And then the biopsies of the duodenal bulb and the second part of the duodenum are obtained. And you received the pathology report that indicates that the biopsies noted significant villous blunting and increased intraepithelial lymphocytes, which in combination with her significantly elevated TTG IgA confirms her diagnosis of celiac disease. With that sith, can you conclude our episode today on the approach to diagnosis of celiac disease with some RTL pearls?

[Dr. Sith Saker]

Absolutely. I think the biggest thing is when you think about celiac disease. I think, number one, anytime you have a patient with iron deficiency deficiency anemia, celiac disease should be something you screen for with serologies. Other things can be sort of non specific GI symptoms as well. We often see people with bloating can present with celiac disease and then even sort of food sensitivities and even sort of diarrhea can also present as celiac disease. So just having a high suspicion and screening for it with serologies is important. And then in terms of workup, you want to send the TTG iga, and anytime you're sending that, you want to send the total IgA as well to screen for IgA deficiency. And as prior, if there is IgA deficiency, then you want to use an IG modality, either TTG IgG, or you want to use the deaminated gliadin protein IgG. And then in these discordant results where you have serology that's positive, biopsy negative or even sometimes you get biopsies are positive and the celiac serologies are negative, then you can use the HLA DQ2, DQ8 genetic testing to see if negative it excludes celiac disease. If positive, then you need to do more testing and then the biggest thing and sort of the thing see very often actually in GI clinics that it's really important for the patients to continue on gluten until their diagnostic upper endoscopy because that really increases the diagnostic yield of biopsies.

[Navin]

Thank you, Sith. Those are awesome pearls. I think you gave us one extra. We usually do three and you gave us a bonus one. So thank you for all that. I had an awesome time discussing with you how to diagnose celiac disease and I look forward to having you back to discuss the management of celiac disease very soon.

[Dr. Sith Saker]

Look forward to being back on.

[Navin]

Thanks so much, Seth and to our RTL listeners, thank you for coming for another episode and we'll see you soon.