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Cow’s milk protein allergy could be the culprit when some children don’t recover on the gluten-free diet

January 27, 2023

Eliminating cow’s milk leads to rapid return to normal in asymptomatic kids whose blood test and biopsy results previously showed ongoing celiac disease damage, researchers found

By Amy Ratner, director of scientific affairs

An allergy to cow’s milk protein might explain why some children with celiac disease do not completely recover on the gluten-free diet, according to researchers from the University of Chicago.

In children who have no symptoms while following the gluten-free diet but whose celiac disease blood test results are positive and biopsies show ongoing intestinal damage, cow’s milk protein can be to blame, the University of Chicago Celiac Disease Center researchers and colleagues from New Mexico and Italy found.

Typically, positive tissue transglutaminase IgA (TTG) and damage to the absorbing lining of the intestine would be attributed to celiac disease itself, and the children assumed to be getting gluten into their gluten-free diet. When these conditions persist despite a very strictly controlled and monitored gluten-free diet, the children are thought to have non-responsive or, more rarely, refractory celiac disease.

Four girls recover

But in the journal, the Annals of Pediatrics, researchers describe the cases of four girls whose blood test results “rapidly and completely” returned to normal when they followed a diet that eliminated cow’s milk protein in addition to the gluten-free diet. Also, the two girls who had follow-up biopsies had normal results.

The case studies demonstrate that a non-immunoglobulin E (IgE) mediated cow’s milk protein allergy that occurs at the same time as celiac disease “may be responsible for some nonresponsive celiac disease, and a cow’s milk [free] and gluten-free diet should be tried before labeling a patient refractory,” the researchers wrote. In an IGE-mediated allergy, reactions, which are typically immediate, are caused by an allergen-specific immunoglobulin E (IgE) antibody. 

Additionally, in a follow-up to the case study, one of the children reintroduced cow’s milk protein after 18 months and continued to have normal blood test and biopsy results. This shows that unlike the life-long inflammatory response to gluten seen in celiac disease, the inflammatory response to cow’s milk protein is transient, the researchers wrote in a follow-up letter to the editor also published in the journal. “Tolerance can be achieved following prolonged but temporary elimination from the diet,” they wrote.

How the case studies were done

Data was collected on symptoms, growth, laboratory results and biopsy results of the four children who were thought to have non-responsive celiac disease. In addition to TTG, the children were tested for and found to have positive Endomysial IgA (EMA), another celiac disease antibody. They all had damage to the villi in the intestine and elevated intraepithelial lymphocytes, signs of active celiac disease.

Previous research had described a patient with celiac disease who had persistently elevated TTG who eliminated milk protein from her diet due to symptoms caused by drinking milk and a test that showed the child had an allergy to it. Her TTG test results were normal for the first time after she took milk out of her diet. “This possible association inspired a trial of a cow’s milk and gluten-free diet in our group of patients with non-responsive celiac disease,” the authors of the new case studies wrote.

Medical histories

In the case studies, one a child diagnosed at 20-months-old had no symptoms and was growing normally but had continued high levels of gluten antibodies when tested at 6-month intervals despite repeated reviews of her diet by a dietitian. Other possible causes of elevated TTG and intestinal damage, including thyroid, autoimmune and inflammatory conditions were ruled out.

Intestinal damage was also found when she had a repeat biopsy after 18 months on the gluten-free diet. Two years after her diagnosis, the girl started a very strict gluten-elimination diet that included only unprocessed gluten-free food. However, her blood test results and a third biopsy were still positive for signs of celiac disease activity. She continued to be asymptomatic and to grow and was monitored for 18 months. Four years into her gluten-free diet, cow’s milk protein was eliminated from her diet. One year later, her blood test results and biopsy were normal for the first time since diagnosis.

The other three children had similar medical histories. In one case, oats were taken out of the child’s diet to eliminate the possibility of cross contamination. The gluten-elimination diet was started for a second child. Another was prescribed oral steroids that resulted in a drop in TTG levels, though they increased when the steroids were discontinued.  All four girls continued to have elevated TTG levels until cow’s milk was eliminated from their diets. This was followed by improvement and finally normal blood test results, and when a biopsy was performed, normal findings as well.

Cow’s milk protein allergy is different from the intolerance to lactose, the sugar found in milk and milk products, which sometimes occurs with celiac disease and resolves after diagnosis and adoption of the  gluten-free diet.

An emerging phenomenon

The association between a cow’s milk protein allergy and ongoing active celiac disease is an emerging phenomenon so the numbers will start out small until it becomes more widely recognized, said Hilary Jericho, MD, a case study researcher at the Chicago celiac center who recently became the medical director of the Center for Pediatric IBD & Celiac Disease at Stanford University. In the four weeks since she has been at Stanford, a child with possible refractory celiac disease has been identified, and a trial cow’s milk protein free diet is planned.

While the Chicago researchers might be one of the first groups to report an association between celiac disease and cow’s milk protein allergy, the concept of coinciding food protein allergies in celiac disease is found in studies published since 1972, Jericho noted. Almost all report on a small number of patients as the phenomenon is not common, but one that should be considered when there is persistent elevation of celiac disease blood test and ongoing inflammation, she said.

The European Society for Pediatric Gastroenterology Hepatology and Nutrition recommends  a search for alternate causes of an apparent refractory celiac disease in these children, including cow’s milk protein allergy.


Five to 19 percent of children with celiac disease have persistent damage to the intestine despite following the gluten-free diet for one year, the case study researchers wrote. In most cases, this is thought to be related to inadvertent gluten ingestion. Consequently, the gluten-elimination diet can be used to further eliminate the possibility of gluten contamination, they note.

“We now propose that in pediatric cases of apparent unresponsiveness in spite of the highly controlled diet, the possibility of cow’s milk protein allergy should be considered and evaluated,” they concluded.

For children with ongoing elevated TTG tests and biopsy evidence of inflammation despite following a strict gluten-free diet for an extended time, Jericho recommends an additional evaluation for other possible causes, followed by a four-to-six week trial of a diet that also excludes cow’s milk protein.

While restrictive, a trial of the cow’s milk protein free diet has little risk under the guidance of a trained dietitian, and there is evidence that cow’s milk can be returned to the diet with time, she said. “It seems to be a safe, and relatively easy, approach to treat possible refractory celiac disease before turning to alternative treatment options such as the use of immunosuppressive therapies, which is currently considered to be the standard of care for the treatment of Type I and II refractory celiac disease,” Jericho said.

Mechanism behind the association

“As for the mechanisms of the association, and the unexpected finding that celiac-disease specific autoantibodies are persistently elevated due to cow’s milk protein allergy, we can only speculate,” the case study investigators  wrote.

One possibility, they note, is that ongoing damage to the small intestine associated with celiac disease leads to an increase in permeability in the tissue lining the gut. This could result in increased likelihood of an immune response to various antigens in the diet, including milk protein.

Antigen mimicry is another possible explanation, as casein in milk and the gliadin protein have a similar amino acid sequence, according to the researchers.  Proteins are made of a sequence of amino acids strung together and those that adopt a similar configuration can stimulate a common response from the immune system.

“This hypothesis of antigen mimicry is supported by other studies which have linked milk protein and gluten,” the researchers wrote.

Future directions

Jericho said she is interested in pursuing further research that would help determine a more specific time frame for eliminating cow’s milk protein and reintroducing it. She’s also interested in studying the mechanism behind the association with celiac disease, which could help to identify lab tests to more objectively diagnose a  cow’s milk protein allergy. This could greatly impact clinical care as it would allow for early testing for the allergy and earlier initiation of the diet without the need for a more extensive evaluation for alternate causes of a possible refractory celiac disease, she said.

You can read more about the case studies here and here.


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