Positive TTG antibody and negative EMA antibody

[Wamedh Taj-Aldeen]

I recently reviewed a patient with a positive tissue transglutaminase (tTG) antibody but negative endomysial antibodies (EMA). The patient is asymptomatic, and duodenal biopsies—taken while on a normal gluten-containing diet—were reported as normal.

Given the discordant serology and absence of histological changes, I understand that the probability of coeliac disease is low. However, I would appreciate your guidance on the following:

Is routine follow-up required in such a case?

What is the risk of progression to overt coeliac disease in the future?

Would HLA DQ2/DQ8 typing be useful here to help guide long-term management or exclude the diagnosis confidently?

I would be grateful for your thoughts.

[trents]

Welcome to celiac.com, @Wamedh Taj-Aldeen!

Just curious, what is your relationship to the patient? Are you the attending physician? A medical student? A consulted physician?

Was a total IGA test ordered? Some physicians are under the dated and mistaken impression that such is only necessary in young children. If total IGA is low, other IGA antibody numbers will be artificially depressed. By the way, it is not unusual to have a positive TTG-IGA and a negative EMA.

Are the TTG-IGA numbers borderline high or unequivocally high? There are other diseases and medical conditions that can cause elevated TTG-IGA numbers besides celiac disease but when this is the case, the numbers are usually not dramatically elevated.

It can also be the case that villous damage was patchy and affected areas were missed during the biopsy. Or, onset of celiac disease was very recent and villous atrophy has not yet progressed to the point of detectability. 

We also have occasional anecdotal reports in this online community of positive antibody testing with negative histology, as you report. But we also know that gluten intolerance can manifest itself apart from enteropathy. It can damage other organ systems. Many celiacs are of the "silent" type, meaning there is an absence or a relative absence of symptoms until the disease has become advanced and there is significant damage to the villous lining or other organ systems.

But to answer your questions:

1. I would definitely pursue a routine follow-up and recheck of the antibodies. And, I would order a complete celiac panel including total IGA and IGG stuff in say, six months. Sooner if symptoms manifest.

2. It is impossible to say what is the risk of the future development of over celiac disease. I refer you back to my #1 above concerning rechecking. 

3. I would definitely pursue HLA DQ2/DQ8 typing as it can be used as a rule out for celiac disease, though not quite with 100% dependability.

I hope my thoughts prove helpful to you.

Edited July 30, 2025 by trents

[Scott Adams]

This is an interesting case. A positive tissue transglutaminase (tTG) antibody with a negative endomysial antibody (EMA) and normal duodenal histology can present a diagnostic challenge, especially in an asymptomatic patient. While the absence of villous atrophy and negative EMA suggest that the likelihood of active celiac disease is low at this time, such serological discordance may still warrant monitoring. Some individuals may be in the early stages of celiac disease, often referred to as potential celiac disease, particularly if they carry the HLA-DQ2 or DQ8 haplotypes. HLA typing can be quite helpful in this situation; a negative result would virtually rule out celiac disease, whereas a positive result may justify periodic follow-up to monitor for evolving disease. The risk of progression to overt celiac disease is not well defined but appears to be higher in children, those with a family history, or those with autoimmune conditions. In this case, routine follow-up including repeat serology and consideration of symptoms or new risk factors over time would be a reasonable and cautious approach.

For people with celiac disease hidden gluten in their diets is the main cause of elevated Tissue Transglutaminase IgA Antibodies (tTG-IgA), but there are other conditions, including cow's milk/casein intolerance, that can also cause this, and here is an article about the other possible causes:

 

 

 

[knitty kitty]

Welcome to the forum, @Wamedh Taj-Aldeen,

How is the patient's thyroid?  

You could check for thiamine deficiency which can cause the thyroid to either become hyper or hypo. 

TTg IgA can be high in both hyperthyroidism and hypothyroidism.  tTg IgA can also be high if patient is taking medications to stimulate the thyroid as in hypothyroidism.  

Thanks for visiting!  Keep us posted!

Edited July 31, 2025 by knitty kitty
Typo correction

[Wamedh Taj-Aldeen]

Thanks for your response and thoughts. Total IgA is normal. HLA DQ2/DQ8 came as heterozygous and the interpretation of the lab that the risk of coeliac disease is mild to moderate. Thyroid function test is normal. I agree that the best way is to repeat tTG antibodies in 6 months time as the result was not massively high.  

[knitty kitty]

You're welcome!

Be sure the patient eats at least ten grams of gluten per day for a minimum of two weeks prior to repeating antibody testing.  

Some people unconsciously reduce the amount of gluten in their diet because the feel unwell.  Three grams of gluten per day is sufficient to produce symptoms.  Only at ten grams or more is the immune system provoked to raise the antibody production high enough so that the antibodies leave the digestive tract and enter the blood stream where they can be measured.  

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